Inhibitors of store operated calcium release

ABSTRACT

Described herein are compounds and pharmaceutical compositions containing such compounds, which modulate the activity of store-operated calcium (SOC) channels. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases, disorders or conditions that would benefit from inhibition of SOC channel activity.

CROSS-REFERENCE

This application claims the benefit of U.S. provisional application Ser.Nos. 61/108,221 filed Oct. 24, 2008; 61/104,210, filed Oct. 9, 2008;61/104,194, filed Oct. 9, 2008; 61/104,189, filed Oct. 9, 2008;61/104,187, filed Oct. 9, 2008; 61/104,151, filed Oct. 9, 2008; and61/102,643, filed Oct. 3, 2008 all of which are incorporated byreference in their entirety.

FIELD OF THE INVENTION

Described herein are compounds, pharmaceutical compositions andmedicaments that include such compounds, and methods of using suchcompounds to modulate store operated calcium (SOC) channel activity.

BACKGROUND OF THE INVENTION

Calcium plays a vital role in cell function and survival. For example,calcium is a key element in the transduction of signals into and withincells. Cellular responses to growth factors, neurotransmitters, hormonesand a variety of other signal molecules are initiated throughcalcium-dependent processes.

Virtually all cell types depend in some manner upon the generation ofcytoplasmic Ca²⁺ signals to regulate cell function, or to triggerspecific responses. Cytosolic Ca²⁺ signals control a wide array ofcellular functions ranging from short-term responses such as contractionand secretion to longer-term regulation of cell growth andproliferation. Usually, these signals involve some combination ofrelease of Ca²⁺ from intracellular stores, such as the endoplasmicreticulum (ER), and influx of Ca²⁺ across the plasma membrane. In oneexample, cell activation begins with an agonist binding to a surfacemembrane receptor, coupled to phospholipase C(PLC) through a G-proteinmechanism. PLC activation leads to the production of inositol1,4,5-triphosphate (IP₃), which in turn activates the IP₃ receptorcausing release of Ca²⁺ from the ER. The fall in ER Ca²⁺ then signals toplasma membrane store-operated calcium (SOC) channels.

Store-operated calcium (SOC) influx is a process in cellular physiologythat controls such diverse functions such as, but not limited to,refilling of intracellular Ca²⁺ stores (Putney et al. Cell, 75, 199-201,1993), activation of enzymatic activity (Fagan et al., J. Biol. Chem.275:26530-26537, 2000), gene transcription (Lewis, Annu. Rev. Immunol.19:497-521, 2001), cell proliferation (Nunez et al., J. Physiol. 571.1,57-73, 2006), and release of cytokines (Winslow et al., Curr. Opin.Immunol. 15:299-307, 2003). In some nonexcitable cells, e.g., bloodcells, immune cells, hematopoietic cells, T lymphocytes and mast cells,SOC influx occurs through calcium release-activated calcium (CRAC)channels, a type of SOC channel.

The calcium influx mechanism has been referred to as store-operatedcalcium entry (SOCE). Stromal interaction molecule (STIM) proteins arean essential component of SOC channel function, serving as the sensorsfor detecting the depletion of calcium from internal stores and foractivating SOC channels.

SUMMARY OF THE INVENTION

Presented herein are isoxazolecarboxylicacidbenzylamides having thegeneral structure:

and compositions that include such compounds and methods for usethereof, for modulating intracellular calcium.

Also presented herein are diphenylazetinones having the generalstructure:

and compositions that include such compounds and methods for usethereof, for modulating intracellular calcium.

Further, presented herein are phenylbenzenesulfonamides having thegeneral structure:

and compositions that include such compounds and methods for usethereof, for modulating intracellular calcium.

Presented herein are dithiophenacrylicacidesters having the generalstructure:

and compositions that include such compounds and methods for usethereof, for modulating intracellular calcium.

Also presented herein are sulfonyltetrahydroisoquinolines having thegeneral structure:

and compositions that include such compounds and methods for usethereof, for modulating intracellular calcium.

Further, presented herein are pyrido-indoles having the generalstructure:

and compositions that include such compounds and methods for usethereof, for modulating intracellular calcium.

Also described herein are compounds of Formula (I)-(XV) and Group A,compositions that include such compounds, and methods of use thereof,for modulating intracellular calcium. In another aspect, compounds ofFormula (I)-(XV) and Group A modulate intracellular calcium byinhibition of store operated calcium channel activity. In a furtheraspect, compounds of Formula (I)-(XV) and Group A modulate intracellularcalcium by preventing the activity of activated store operated calciumchannel complexes. In one aspect, compounds of Formula (I)-(XV) andGroup A inhibit activation of store operated channels. In anotheraspect, compounds of Formula (I)-(XV) and Group A inhibit activation ofcalcium-release activated calcium channels. In yet another aspect,compounds of Formula (I)-(XV) and Group A modulate an activity of,modulate an interaction of, or modulate the level of, or bind to, orinteract with at least one protein of the SOC channel complex. In oneaspect, compounds of Formula (I)-(XV) and Group A modulate an activityof, modulate an interaction of, or modulate the level of, or bind to, orinteract with at least one protein of the CRAC channel complex. Inanother aspect, a compound of Formula (I)-(XV) and Group A is aselective inhibitor of SOC channel activity. In one aspect, compounds ofFormula (I)-(XV) and Group A are selective inhibitors of CRAC channelactivity.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store-operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (I)-(XV) or Group A; or pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof.

In another aspect, described herein is a method of modulating calciumrelease activated calcium channel (CRAC) activity in a mammal comprisingadministering a compound of Formula (I)-(XV) or Group A; orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof.

Also described herein is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A; or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof.

Also described herein is a method of inhibiting store-operated calciumentry (SOCE) activation of nuclear factor of activated T cells (NFAT) ina mammal comprising administering a compound of Formula (I)-(XV) orGroup A; or pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof.

Also provided herein is a method of decreasing cytokine expression byinhibiting the store-operated calcium entry activation of NFAT in amammal comprising administering a compound of Formula (I)-(XV) or GroupA; or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

Any combination of the groups described above for the various variablesis contemplated herein.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (I):

wherein:

-   -   Y is cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,        heteroarylalkyl; wherein the cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,        heteroarylalkyl is optionally substituted with at least one R₃;    -   R₁ is H, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl,        and benzyl;    -   L is a bond, C(O), C₁-C₆alkyl, C₁-C₆alkenylene, heteroalkyl;    -   X is C₁-C₆alkyl, aryl or heteroaryl; wherein C₁-C₆ alkyl, aryl        or heteroaryl is optionally substituted with at least one R₃;    -   R₂ is aryl, arylalkyl, heteroaryl, heteroarylalkyl; wherein the        aryl, arylalkyl, heteroaryl, and heteroarylalkyl is optionally        substituted with at least one R₃;    -   R₃ is independently selected from F, Cl, Br, I, —CN, —NO₂, —OH,        —CF₃, —OCF₃, —OR⁸, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R⁸, —S(═O)₂N(R⁹)₂,        —N(R⁹)S(═O)₂N(R⁹)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R⁸,        —S(═O)₂NHC(═O)R⁸, —N(R⁹)₂, —N(R⁹)C(═O)R⁸, —N(R⁹)C(═O)N(R⁹)₂,        —N(R⁹)C(═O)OR⁸, —CO₂R⁹, —C(═O)R⁸, —OC(═O)R⁸, —OC(═O)N(R⁹)₂,        —CON(R⁹)₂, —SR⁸, —S(═O)R⁸, and —S(═O)₂R⁸;    -   each R⁸ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; and    -   each R⁹ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (II):

wherein:

-   -   L is a bond, C₁-C₆alkyl, C₁-C₆alkenylene, heteroalkyl;    -   X is aryl or heteroaryl; wherein aryl or heteroaryl is        optionally substituted with at least one R₃;    -   R₁ is selected from H, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₃-C₈cycloalkyl, phenyl, and benzyl;    -   R₂ is aryl, arylalkyl, heteroaryl, heteroarylalkyl; wherein the        aryl, arylalkyl, heteroaryl, heteroarylalkyl is optionally        substituted with at least one R₃;    -   R₄ and R₁₀ are each independently selected from H, F, Cl, Br, I,        —CN, —NO₂, —OH, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₆ is selected from H, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₃, R₅ and R₇ are each independently selected from H, F, Cl, Br,        I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In another embodiment, is a compound of Formula (III):

wherein:

-   -   L and L₁ are each independently a bond, C₁-C₆alkyl,        C₁-C₆alkenylene, heteroalkyl;    -   X and X₁ are each independently aryl or heteroaryl; wherein aryl        or heteroaryl is optionally substituted with at least one R₃;    -   R₁ is selected from H, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₃-C₈cycloalkyl, phenyl, and benzyl;    -   R₄ and R₁₀ are each independently selected from H, F, Cl, Br, I,        —CN, —NO₂, —OH, CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₆ is selected from H, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₃, R₅ and R₇ are each independently selected from H, F, Cl, Br,        I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (IV):

wherein:

-   -   X and Z are each independently selected from a group consisting        of aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein        aryl, heteroaryl, arylalkyl, or heteroarylalkyl are optionally        substituted with at least one R₁;    -   Y is aryl or heteroaryl substituted with at least one R₃        selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —SR_(s), —S(═O)R₈, and —S(═O)₂R₈;    -   R₁ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (V):

wherein:

-   -   Z is selected from a group consisting of aryl, heteroaryl,        arylalkyl, or heteroarylalkyl, wherein aryl, heteroaryl,        arylalkyl, or heteroarylalkyl are optionally substituted with at        least one R₁₃;    -   R₂, R₄, R₆, R₇, R₁₀, R₁₁, R₁₂, and R₁₃ are each independently        selected from a group consisting of H, F, Cl, Br, I, —CN, —NO₂,        —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₃ is selected from F, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₁ and R₅ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₂-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store-operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (VI):

wherein:

-   -   X is heterocycloalkyl, aryl, arylheteroalkyl, heteroaryl,        arylalkyl, heteroarylalkyl, 9H-xanthene; wherein        heterocycloalkyl, aryl, arylheteroalkyl, heteroaryl, arylalkyl,        heteroarylalkyl, 9H-xanthene are optionally substituted with at        least one R₂;    -   Y is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₈, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₁ and R₃ are each independently selected from hydrogen,        C₁-C₆alkyl, phenyl or benzyl;    -   R₂ is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,        —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)(R₁₀),        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₁₀ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl or    -   R₉ and R₁₀ and the nitrogen atom to which they are attached form        a 3-8 membered heterocyclic ring; or pharmaceutically acceptable        salt, pharmaceutically acceptable solvate, or pharmaceutically        acceptable prodrug thereof.

In one embodiment is a compound of Formula (VII):

wherein:

-   -   X is heterocycloalkyl, aryl, arylheteroalkyl, heteroaryl,        arylalkyl, heteroarylalkyl, 9H-xanthene; wherein        heterocycloalkyl, aryl, arylheteroalkyl, heteroaryl, arylalkyl,        heteroarylalkyl, 9H-xanthene are optionally substituted with at        least one R₂;    -   Y is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₈, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₁ and R₃ are each independently selected from hydrogen,        C₁-C₆alkyl, phenyl or benzyl;    -   R₄, R₆, R₇, and R₁₂ are each independently selected from H, F,        Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, OR₁₁, C₂-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)(R₁₀), —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₂ is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,        —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)(R₁₀),        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₅ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)(R₁₀),        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₁₀ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl or    -   R₉ and R₁₀ and the nitrogen atom to which they are attached form        a 3-8 membered heterocyclic ring;    -   each R₁₁ is independently selected from H, C₂-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In another aspect, described herein is a method of modulatingstore-operated calcium (SOC) channel activity comprising contacting thestore-operated calcium (SOC) channel complex, or portion thereof, with acompound of Formula (VIII):

wherein:

-   -   X is H, NR₉R₉, —OR₄, —OC₁-C₆alkylaryl; C₁-C₆alkyl, C₁-C₆alkenyl,        C₁-C₆heteroalkyl, aryl, heteroaryl; wherein C₁-C₆alkyl,        C₁-C₆alkenyl, C₁-C₆heteroalkyl, aryl and heteroaryl is        optionally substituted with at least one R₃;    -   R₁ and R₂ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₃ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₄ is C₁-C₆alkyl-C(═O)N(R₉)(R₁₀) or C₁-C₆alkyl-C(═O)OR₉;    -   R₅ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, and optionally substituted        heteroaryl;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; wherein        phenyl and benzyl are optionally substituted with at least one        R₅;    -   each R₁₀ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment, is a compound of Formula (IX):

wherein:

-   -   R₁ and R₂ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₃ is selected from H, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₃-C₈cycloalkyl, phenyl, and benzyl;    -   R₄ and R₁₀ are each independently selected from F, Br, I, —CN,        —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₅ and R₇ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₆ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or a pharmaceutically acceptable prodrug thereof.

In another embodiment, is a compound of Formula (X):

wherein:

-   -   R₁ and R₂ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₅ and R₇ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —OCF₃, —OR₁₀, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₄, R₆, and R₁₀ are each independently selected from F, Cl, Br,        I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   R₁₀ is independently selected from H, C₂-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store-operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (XI):

wherein:

-   -   X is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein        cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally        substituted with at least one R₄;    -   R₂ and R₃ are each independently H, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; or    -   R₂ and R₃ together with the nitrogen atom to which they are        attached form a 3-8 membered heterocycloalkyl ring or a        6-membered heteroaryl ring;    -   R₁ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₄ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment, is a compound of Formula (XII):

wherein:

-   -   X is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein        cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally        substituted with at least one R₄;    -   R₂ is selected from H, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R₁ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₃ and R₇ are each independently selected from H, F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₄ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₆ and R₁₀ are each independently selected from H, F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₅ is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,        —OCF₃, —OR₉, C₁-C₃alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (XIII):

wherein:

-   -   R₂ and R₃ are each independently H, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; or    -   R₂ and R₃ together with the nitrogen atom to which they are        attached form a 3-8 membered heterocycloalkyl ring or a        6-membered heteroaryl ring;    -   R₁ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₅, R₆, R₁₀, and R₁₁ are each independently selected from H, F,        Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted O-aryl, optionally        substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈₅—OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₇ is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,        —OCF₃, —OR₉, C₂-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store-operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (XIV):

wherein:

-   -   X is cycloalkyl, heterocycloalkyl, aryl, and heteroaryl wherein        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally        substituted with at least one R₃;    -   Y is a bond, C₁-C₆alkyl, C₂-C₆alkenyl, NR₂, O, S,        NR₂(C₁-C₆alkyl), O(C₁-C₆alkyl), S(C₁-C₆alkyl),        NR₂(C₂-C₆alkenyl), O(C₂-C₆alkenyl), S(C₂-C₆alkenyl); wherein        C₁-C₆alkyl and C₂-C₆alkenyl are optionally substituted with at        least one R₃;    -   Z is cycloalkyl, heterocycloalkyl, aryl, and heteroaryl wherein        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally        substituted with at least one R₄;    -   each R₁ is independently selected from H, F, Cl, Br, I, —CN,        —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₂ is H, C₁-C₆alkyl, and C₃-C₈cycloalkyl;    -   R₃ and R₄ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈; or    -   two R₃ together with the atoms to which they are attached form a        heterocycloalkyl group having at least one O, NH, or S;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment, is a compound having the structure of Formula (XV):

wherein:

-   -   X is cycloalkyl, heterocycloalkyl, aryl, and heteroaryl wherein        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally        substituted with at least one R₃;    -   Y is a bond, C₁-C₆alkyl, C₂-C₆alkenyl, NR₂, O, S,        NR₂(C₁-C₆alkyl), O(C₁-C₆alkyl), S(C₁-C₆alkyl),        NR₂(C₂-C₆alkenyl), O(C₂-C₆alkenyl), S(C₂-C₆alkenyl); wherein        C₁-C₆alkyl and C₂-C₆alkenyl are optionally substituted with at        least one R₃;    -   each R₁ is independently selected from H, F, Cl, Br, I, —CN,        —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₂ is H, C₁-C₆alkyl, and C₃-C₈cycloalkyl;    -   R₃ and R₄ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈; or    -   two R₃ together with the atoms to which they are attached form a        heterocycloalkyl group having at least one O, NH, or S;    -   R₅ is selected from Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store-operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (I)-(XV) and Group A, or pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof. In one embodiment, the contacting occurs in vitro. Inanother embodiment, the contacting occurs in vivo. In one embodiment,the compound of Formula (I)-(XV) and Group A modulates an activity of,modulates an interaction of, or modulates the level of, or binds to, orinteracts with at least one portion of the store operated calciumchannel complex selected from stromal interaction molecules (STIM)family of proteins. In one embodiment, the compound of Formula (I)-(XV)and Group A modulates an activity of, modulates an interaction of, ormodulates the level of, or binds to, or interacts with at least oneportion of STIM1 or STIM2. In one embodiment, modulating store operatedcalcium channel activity with a compound of Formula (I)-(XV) and Group Ainhibits store-operated calcium entry (SOCE). In another embodiment, thestore operated calcium channel complex is calcium-release activatedcalcium (CRAC) channel complex. In one embodiment, modulating calciumrelease activated calcium (CRAC) activity with a compound of Formula(I)-(XV) and Group A inhibits the electrophysiological current(I_(CRAC)) directly associated with activated CRAC channels.

In another aspect, described herein is a method of modulating calciumrelease activated calcium channel (CRAC) activity in a mammal comprisingadministering a compound of Formula (I)-(XV) and Group A, orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof. In one embodiment, thecompound of Formula (I)-(XV) and Group A modulates an activity of,modulates an interaction of, or modulates the level of, or binds to, orinteracts with at least one component of the calcium release activated(CRAC) channel complex selected from stromal interaction molecules(STIM) family of proteins. In one embodiment, the compound of Formula(I) modulates an activity of, modulates an interaction of, or modulatesthe level of, or binds to, or interacts with STIM1 or STIM2. In oneembodiment, modulating calcium release activated calcium (CRAC) channelactivity with a compound of Formula (I)-(XV) and Group A inhibitsstore-operated calcium entry (SOCE). In one embodiment, modulatingcalcium release activated calcium (CRAC) channel activity with acompound of Formula (I)-(XV) and Group A inhibits theelectrophysiological current (I_(CRAC)) directly associated withactivated CRAC channels. In one embodiment, the compound of Formula(I)-(XV) and Group A inhibits SOCE with an IC₅₀ below about 10 μM. Inyet another embodiment, the compound of Formula (I)-(XV) and Group Ainhibits electrophysiological current (I_(CRAC)) directly associatedwith activated CRAC channels at a concentration below about 10 μM.

Also described herein is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) and Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof. In one aspect, the compoundof Formula (I)-(XV) and Group A modulates the activity of, modulates aninteraction of, or binds to, or interacts with a mammalian STIM1protein, or a mammalian STIM2 protein. In one embodiment, the disease,disorder or condition in a mammal is selected from diseases/disordersinvolving inflammation, glomerulonephritis, uveitis, hepatic diseases ordisorders, renal diseases or disorders, chronic obstructive pulmonarydisease, rheumatoid arthritis, inflammatory bowel disease, psoriasis,vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease,allergic rhinitis, vaginitis, interstitial cystitis, scleroderma,osteoporosis, eczema, organ transplant rejection, allogeneic orxenogeneic transplantation, graft rejection, graft-versus-host disease,lupus erythematosus, type I diabetes, pulmonary fibrosis,dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolyticanemia, cystic fibrosis, chronic relapsing hepatitis, primary biliarycirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis,asthma, multiple sclerosis, Sjogren's syndrome, cancer and otherproliferative diseases, and autoimmune diseases or disorders. In yetanother embodiment, the method further comprises administering to themammal a second therapeutic agent. In one embodiment, the secondtherapeutic agent is selected from immunosuppressants, glucocorticoids,non-steroidal anti-inflammatory drugs, Cox-2-specific inhibitors,leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine,hydroxychloroquinine, minocycline, anti-TNF-α agents, abatacept,anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines,antihistamines, antileukotrienes, beta-agonists, theophylline, andanticholinergics. In another embodiment, the second therapeutic agent isselected from tacrolimus, cyclosporin, rapamicin, methotrexate ,cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, orFTY720, prednisone, cortisone acetate, prednisolone, methylprednisolone,dexamethasone, betamethasone, triamcinolone, beclometasone,fludrocortisone acetate, deoxycorticosterone acetate, aldosterone,aspirin, salicylic acid, gentisic acid, choline magnesium salicylate,choline salicylate, choline magnesium salicylate, choline salicylate,magnesium salicylate, sodium salicylate, diflunisal, carprofen,fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen,nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin,diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate,meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, celecoxib,rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502,JTE-522, L-745,337 and NS398, leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,infliximab, etanercept, adalimumab, abatacept, anakinra, interferon-β,interferon-γ, interleukin-2, allergy vaccines, antihistamines,antileukotrienes, beta-agonists, theophylline, and anticholinergics.

Also described herein is a method of inhibiting store-operated calciumentry (SOCE) activation of nuclear factor of activated T cells (NFAT) ina mammal comprising administering a compound of Formula (I), (II), or(III) or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof. In oneembodiment, the compound of Formula (I)-(XV) and Group A modulates aninteraction of, or modulates the level of, or binds to, or interactswith a mammalian STIM1 protein, or a mammalian STIM2 protein.

Also provided herein is a method of decreasing cytokine expression byinhibiting the store-operated calcium entry activation of NFAT in amammal comprising administering a compound of Formula (I)-(XV) and GroupA, or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof. In oneembodiment, the compound of Formula (I)-(XV) and Group A modulates aninteraction of, or modulates the level of, or binds to, or interactswith a mammalian STIM1 protein or a mammalian STIM2 protein. In oneembodiment, the cytokine is selected from IL-2, IL-3, IL-4, IL-5, IL-6,IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17,IL-18, IL-1α, IL-1β, IL-1 RA, granulocyte colony stimulating factor(G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF),oncostatin M, erythropoietin, leukemia inhibitory factor (LIF),interferons, gamma-interferon (γ-IFN), B7.1 (CD80), B7.2 (B70, CD86),TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand,4-1BBL, Trail, and migration inhibitory factor (MIF).

In one aspect, described herein is the use of a compound of Formula(I)-(XV) and Group A, or pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof, for the formulation of a medicament for the modulationof store operated calcium (SOC) channel activity in a subject or for thetreatment of a disease, disorder or condition in a subject that wouldbenefit from the modulation of store operated calcium (SOC) channelactivity. In one embodiment, the compound of Formula (I)-(XV) and GroupA inhibits store operated calcium entry (SOCE). In another embodiment,the store operated calcium channel activity is calcium release activatedcalcium channel activity.

Also described is an article of manufacture, comprising packagingmaterial, a compound of Formula (I)-(XV) and Group A, or composition, orpharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, which is effective forinhibiting calcium release-activated calcium (CRAC) channel activity, orfor the treatment, prevention or amelioration of one or more symptoms ofa disease, disorder or condition that would benefit from the inhibitionof calcium release-activated calcium (CRAC) channel activity, within thepackaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, pharmaceuticallyacceptable prodrug, or pharmaceutically acceptable solvate thereof, isused for the inhibition of calcium release-activated calcium (CRAC)channel activity, or for the treatment, prevention or amelioration ofone or more symptoms of a disease, disorder or condition that wouldbenefit from the inhibition of calcium release-activated calcium (CRAC)channel activity. In one embodiment, the compound of Formula (I)-(XV)and Group A inhibits store operated calcium entry (SOCE).

In one aspect, described herein is a pharmaceutical compositioncomprising a pharmaceutically acceptable diluent, excipient or binder,and a compound of Formula (I)-(XV) and Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable prodrug, orpharmaceutically acceptable solvate thereof.

In one embodiment, provided herein is a pharmaceutical composition,which includes an effective amount of a compound provided herein, and apharmaceutically acceptable excipient. In a further embodiment, providedare compositions further including a second pharmaceutically activeingredient.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds described herein.

In any of the aforementioned aspects are further embodiments thatinclude single administrations of the effective amount of the compoundof Formula (I)-(XV) and Group A, including further embodiments in which:(i) the compound of Formula (I)-(XV) and Group A is administered once;(ii) the compound of Formula (I)-(XV) and Group A is administered to themammal multiple times over the span of one day; (iii) continually; or(iv) continuously.

In any of the aforementioned aspects are further embodiments thatinclude multiple administrations of the effective amount of the compoundof Formula (I)-(XV) and Group A, including further embodiments in which(i) the compound of Formula (I)-(XV) and Group A is administered in asingle dose; (ii) the time between multiple administrations is every 6hours; (iii) the compound of Formula (I)-(XV) and Group A isadministered to the mammal every 8 hours. In further embodiments, themethod comprises a drug holiday, wherein the administration of thecompound of Formula (I)-(XV) and Group A is temporarily suspended or thedose of the compound of Formula (I)-(XV) and Group A being administeredis temporarily reduced; at the end of the drug holiday, dosing of thecompound of Formula (I)-(XV) and Group A is resumed. In someembodiments, the length of the drug holiday varies from 2 days to 1year.

In one embodiment, compounds of Formula (I)-(XV) and Group A describedherein are administered to a human. In some embodiments, compounds ofFormula (I)-(XV) and Group A described herein are orally administered.

Compounds provided herein are used for modulating intracellular calcium.In one embodiment, compounds provided herein modulate SOC channelactivity. In one embodiment, compounds provided herein modulate CRACchannel activity. In another embodiment, compounds provided hereinmodulate STIM protein activity. In another embodiment, compoundsprovided herein modulate Orai protein activity. In another embodiment,compounds provided herein modulate the functional interactions of STIMproteins with Orai proteins. In another embodiment, compounds providedherein reduce the number of functional SOC channels. In anotherembodiment, compounds provided herein reduce the number of functionalCRAC channels. In one embodiment, compounds described herein are SOCchannel blockers. In one embodiment, compounds described herein are CRACchannel blockers.

In one embodiment, compounds of Formula (I)-(XV) and Group A areselective inhibitors of SOCE. In one embodiment, compounds of Formula(I)-(XV) and Group A are selective inhibitors of CRAC channel activity.

Other objects, features and advantages of the compounds, compositions,methods, and uses described herein will become apparent from thefollowing detailed description. It should be understood, however, thatthe detailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 outlines the I_(CRAC) channel pathway.

FIG. 2 shows the typical I_(CRAC) traces in cells stably overexpressinghuman Orai 1 and STIM 1 in response to the voltage stimulus immediatelyafter break-in, before I_(CRAC) is activated, and at 5 min afterI_(CRAC) is fully activated by depletion of intracellular calciumstores.

DETAILED DESCRIPTION

Cellular calcium homeostasis is a result of the summation of regulatorysystems involved in the control of intracellular calcium levels andmovements. Cellular calcium homeostasis is achieved, at least in part,by calcium binding and by movement of calcium into and out of the cellacross the plasma membrane and within the cell by movement of calciumacross membranes of intracellular organelles including, for example, theendoplasmic reticulum, sarcoplasmic reticulum, mitochondria andendocytic organelles including endosomes and lysosomes.

Movement of calcium across cellular membranes is carried out byspecialized proteins. For example, calcium from the extracellular spacecan enter the cell through various calcium channels and a sodium/calciumexchanger and is actively extruded from the cell by calcium pumps andsodium/calcium exchangers. Calcium can also be released from internalstores through inositol trisphosphate or ryanodine receptors and can betaken up by these organelles by means of calcium pumps.

Calcium can enter cells by any of several general classes of channels,including but not limited to, voltage-operated calcium (VOC) channels,store-operated calcium (SOC) channels, and sodium/calcium exchangersoperating in reverse mode. VOC channels are activated by membranedepolarization and are found in excitable cells like nerve and muscleand are for the most part not found in nonexcitable cells. Under someconditions, Ca²⁺ can enter cells via Na⁺—Ca²⁺ exchangers operating inreverse mode.

Endocytosis provides another process by which cells take up calcium fromthe extracellular medium through endosomes. In addition, some cells,e.g., exocrine cells, can release calcium via exocytosis.

Cytosolic calcium concentration is tightly regulated with resting levelsusually estimated at approximately 0.1 μM in mammalian cells, whereasthe extracellular calcium concentration is typically about 2 mM. Thistight regulation facilitates transduction of signals into and withincells through transient calcium flux across the plasma membrane andmembranes of intracellular organelles. There is a multiplicity ofintracellular calcium transport and buffer systems in cells that serveto shape intracellular calcium signals and maintain the low restingcytoplasmic calcium concentration. In cells at rest, the principalcomponents involved in maintaining basal calcium levels are calciumpumps and leaks in the endoplasmic reticulum and plasma membrane.Disturbance of resting cytosolic calcium levels can effect transmissionof such signals and give rise to defects in a number of cellularprocesses. For example, cell proliferation involves a prolonged calciumsignaling sequence. Other cellular processes include, but are notlimited to, secretion, signaling, and fertilization, involve calciumsignaling.

Cell-surface receptors that activate phospholipase C(PLC) createcytosolic Ca²⁺ signals from intra- and extra-cellular sources. Aninitial transient rise of [Ca²⁺]_(i) (intracellular calciumconcentration) results from the release of Ca²⁺ from the endoplasmicreticulum (ER), which is triggered by the PLC product,inositol-1,4,5-trisphosphate (IP₃), opening IP₃ receptors in the ER(Streb et al. Nature, 306, 67-69, 1983). A subsequent phase of sustainedCa²⁺ entry across the plasma membrane then ensues, through specializedstore operated calcium (SOC) channels (in the case of immune cells theSOC channels are calcium release-activated calcium (CRAC) channels) inthe plasma membrane. Store-operated Ca²⁺ entry (SOCE) is the process inwhich the emptying of Ca²⁺ stores itself activates Ca²⁺ channels in theplasma membrane to help refill the stores (Putney, Cell Calcium, 7,1-12, 1986; Parekh et al., Physiol. Rev. 757-810; 2005). SOCE does morethan simply provide Ca²⁺ for refilling stores, but can itself generatesustained Ca²⁺ signals that control such essential functions as geneexpression, cell metabolism and exocytosis (Parekh and Putney, Physiol.Rev. 85, 757-810 (2005).

In lymphocytes and mast cells, activation of antigen or Fc receptorscauses the release of Ca²⁺ from intracellular stores, which in turnleads to Ca²⁺ influx through CRAC channels in the plasma membrane. Thesubsequent rise in intracellular Ca²⁺ activates calcineurin, aphosphatase that regulates the transcription factor NFAT. In restingcells, NFAT is phosphorylated and resides in the cytoplasm, but whendephosphorylated by calcineurin, NFAT translocates to the nucleus andactivates different genetic programmes depending on stimulationconditions and cell type. In response to infections and duringtransplant rejection, NFAT partners with the transcription factor AP-1(Fos-Jun) in the nucleus of “effector” T cells, thereby transactivatingcytokine genes, genes that regulate T cell proliferation and other genesthat orchestrate an active immune response (Rao et al., Annu RevImmunol., 1997; 15:707-47). In contrast, in T cells recognizing selfantigens, NFAT is activated in the absence of AP-1, and activates atranscriptional programme known as “anergy” that suppresses autoimmuneresponses (Macian et al., Transcriptional mechanisms underlyinglymphocyte tolerance. Cell. 2002 Jun. 14; 109(6):719-31). In a subclassof T cells known as regulatory T cells which suppress autoimmunitymediated by self-reactive effector T cells, NFAT partners with thetranscription factor FOXP3 to activate genes responsible for suppressorfunction (Wu et al., Cell, 2006 Jul. 28; 126(2):375-87; Rudensky A Y,Gavin M, Zheng Y. Cell. 2006 Jul. 28; 126(2):253-256).

The endoplasmic reticulum (ER) carries out a variety processes. The ERhas a role as both an agonist-sensitive Ca²⁺ store and sink, proteinfolding/processing takes place within its lumen. Here, numerousCa²⁺-dependent chaperone proteins ensure that newly synthesized proteinsare folded correctly and sent off to the appropriate destination. The ERis also involved in vesicle trafficking, release of stress signals,regulation of cholesterol metabolism, and apoptosis. Many of theseprocesses require intraluminal Ca²⁺, and protein misfolding, ER stressresponses, and apoptosis can all be induced by depleting the ER of Ca²⁺for prolonged periods of time. Because of its role as a source of Ca²⁺,it is clear that ER Ca²⁺ content must fall after stimulation. However,to preserve the functional integrity of the ER, it is vital that theCa²⁺ content does not fall too low or is maintained at a low level.Replenishment of the ER with Ca²⁺ is therefore a central process to alleukaryotic cells. Because a fall in ER Ca²⁺ content activatesstore-operated Ca²⁺ channels in the plasma membrane, a major function ofthis Ca²⁺ entry pathway is believed to be maintenance of ER Ca²⁺ levelsthat are necessary for proper protein synthesis and folding. However,store-operated Ca²⁺ channels have other important roles.

The understanding of store operated calcium entry was provided byelectrophysiological studies which established that the process ofemptying the stores activated a Ca²⁺ current in mast cells called Ca²⁺release-activated Ca²⁺ current or I_(CRAC). I_(CRAC) is non-voltageactivated, inwardly rectifying, and remarkably selective for Ca²⁺. It isfound in several cell types mainly of hemapoietic origin. I_(CRAC) isnot the only store-operated current, and it is now apparent thatstore-operated influx encompasses a family of Ca²⁺-permeable channels,with different properties in different cell types. I_(CRAC) was thefirst store-operated Ca²⁺ current to be described and remains a popularmodel for studying store-operated influx.

Store-operated calcium channels can be activated by any procedure thatempties the stores; it does not seem to matter how the stores areemptied, the net effect is activation of store-operated Ca²⁺ entry.Physiologically, store emptying is evoked by an increase in the levelsof IP₃ or other Ca²⁺-releasing signals followed by Ca²⁺ release from thestores. But there are several other methods for emptying stores. Thesemethods include the following:

-   1) elevation of IP₃ in the cytosol (following receptor stimulation    or, dialyzing the cytosol with IP₃ itself or related congeners like    the nonmetabolizable analog Ins(2,4,5)P₃);-   2) application of the Ca²⁺ ionophore ionomycin to permeabilize the    ER membrane;-   3) dialyzing the cytoplasm with high concentrations of the Ca²⁺    chelators EGTA or BAPTA, which chelate Ca²⁺ that leaks from the    stores and hence prevent store refilling;-   4) exposure to the sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase    (SERCA) inhibitors like thapsigargin, cyclopiazonic acid, and    di-tert-butylhydroquinone which prevent the P-type ATPases from    refilling the stores;-   5) sensitizing the IP₃ receptors to resting levels of InsP₃ with    agents like thimerosal; and-   6) loading membrane-permeable metal Ca²⁺ chelators like    N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylene diamine (TPEN) directly    into the stores.

Through mass action, TPEN lowers free intraluminal Ca²⁺ concentrationwithout changing total store Ca²⁺ such that the storedepletion-dependent signal is generated.

These methods of emptying stores are not devoid of potential problems.The key feature of store-operated Ca²⁺ entry is that it is the fall inCa²⁺ content within the stores and not the subsequent rise incytoplasmic Ca²⁺ concentration that activates the channels. However,ionomycin and SERCA pump blockers generally cause a rise in cytoplasmicCa²⁺ concentration as a consequence of store depletion, and such a risein Ca²⁺ could open Ca²⁺-activated cation channels permeable to Ca²⁺. Oneway to avoid such problems is to use agents under conditions wherecytoplasmic Ca²⁺ has been strongly buffered with high concentrations ofCa²⁺ chelator such as EGTA or BAPTA.

Store-Operated Calcium Entry

Reduced calcium concentration in intracellular calcium stores such asthe endoplasmic reticulum resulting from release of calcium there fromprovides a signal for influx of calcium from the extracellular mediuminto the cell. This influx of calcium, which produces a sustained“plateau” elevation of cytosolic calcium concentration, generally doesnot rely on voltage-gated plasma membrane channels and does not involveactivation of calcium channels by calcium. This calcium influx mechanismis referred to as capacitative calcium entry (CCE), calciumrelease-activated, store-operated or depletion-operated calcium entry.Store-operated calcium entry can be recorded as an ionic current withdistinctive properties. This current is referred to as I_(SOC)(store-operated current) or I_(CRAC) (calcium release-activatedcurrent).

Electrophysiological analysis of store-operated or calciumrelease-activated currents reveals distinct biophysical properties ofthese currents. For example, the current are activated by depletion ofintracellular calcium stores (e.g., by nonphysiological activators suchas thapsigargin, CPA, ionomycin and BAPTA, and physiological activatorssuch as IP₃) and can be selective for divalent cations, such as calcium,over monovalent ions in physiological solutions or conditions, can beinfluenced by changes in cytosolic calcium levels, and can show alteredselectivity and conductivity in the presence of low extracellularconcentrations of divalent cations. The current may also be blocked orenhanced by 2-APB (depending on concentration) and blocked by SKF96365and Gd³⁺ and generally are described as a calcium current that is notstrictly voltage-gated.

Patch-clamp studies in mast cells and Jurkat leukaemic T cells haveestablished the CRAC entry mechanism as an ion channel with distinctivebiophysical characteristics, including a high selectivity for Ca²⁺paired with an exceedingly low conductance. Furthermore, the CRACchannel was shown to fulfill the rigorous criteria for beingstore-operated, which is the activation solely by the reduction of Ca²⁺in the ER rather than by cytosolic Ca²⁺ or other messengers generated byPLC.

Regulation of Store-Operated Calcium Entry by Intracellular CalciumStores

Store-operated calcium entry is regulated by the level of calcium withinan intracellular calcium store. Intracellular calcium stores arecharacterized by sensitivity to agents, which are physiological orpharmacological, which activate release of calcium from the stores orinhibit uptake of calcium into the stores. Different cells have beenstudied in characterization of intracellular calcium stores, and storeshave been characterized as sensitive to various agents, including, butnot limited to, IP₃ and compounds that effect the IP₃ receptor,thapsigargin, ionomycin and/or cyclic ADP-ribose (cADPR).

Accumulation of calcium within endoplasmic reticulum and sarcoplasmicreticulum (SR; a specialized version of the endoplasmic reticulum instriated muscle) storage organelles is achieved throughsarcoplasmic-endoplasmic reticulum calcium ATPases (SERCAs), commonlyreferred to as calcium pumps. During signaling (i.e., when endoplasmicreticulum channels are activated to provide for calcium release from theendoplasmic reticulum into the cytoplasm), endoplasmic reticulum calciumis replenished by the SERCA pump with cytoplasmic calcium that hasentered the cell from the extracellular medium.

Calcium release channels associated with IP₃ and ryanodine receptorsprovide for controlled release of calcium from endoplasmic andsarcoplasmic reticulum into the cytoplasm resulting in transientincreases in cytoplasmic calcium concentration. IP₃ receptor-mediatedcalcium release is triggered by IP₃ formed in the break down of plasmamembrane phosphoinositides through the action of phospholipase Cactivated by binding of an agonist to a plasma membrane Gprotein-coupled receptor. Ryanodine receptor-mediated calcium release istriggered by an increase in cytoplasmic calcium and is referred to ascalcium-induced calcium release (CICR). The activity of ryanodinereceptors (which have affinity for ryanodine and caffeine) may also beregulated by cyclic ADP-ribose.

Thus, the calcium levels in the stores, and in the cytoplasm, fluctuate.For example, ER free calcium can decrease from a range of about 60 toabout 400 μM to about 1 to about 50 μM when HeLa cells are treated withhistamine, an agonist of PLC-linked histamine receptors (Miyawaki et al.(1997) Nature 388:882-887). Store-operated calcium entry is activated asthe free calcium concentration of the intracellular stores is reduced.Depletion of store calcium, as well as a concomitant increase incytosolic calcium concentration, can thus regulate store-operatedcalcium entry into cells.

Cytoplasmic Calcium Buffering

Agonist activation of signaling processes in cells can involve dramaticincreases in the calcium permeability of the endoplasmic reticulum, forexample, through opening of IP₃ receptor channels, and the plasmamembrane through store-operated calcium entry. These increases incalcium permeability are associated with an increase in cytosoliccalcium concentration that are separated into two components: a “spike”of calcium release from the endoplasmic reticulum during activation ofthe IP₃ receptor and a plateau phase which is a sustained elevation ofcalcium levels resulting from entry of calcium into the cytoplasm fromthe extracellular medium. Upon stimulation, the resting intracellularfree calcium concentration of about 100 nM can rise globally to greaterthan 1 μM. The cell modulates these calcium signals with endogenouscalcium buffers, including physiological buffering by organelles such asmitochondria, endoplasmic reticulum and Golgi. Mitochondrial uptake ofcalcium through a uniporter in the inner membrane is driven by the largenegative mitochondrial membrane potential, and the accumulated calciumis released slowly through sodium-dependent and -independent exchangers,and, under some circumstances, the permeability transition pore (PTP).Thus, mitochondria can act as calcium buffers by taking up calciumduring periods of activation and slowly releasing it later. Uptake ofcalcium into the endoplasmic reticulum is regulated by the sarcoplasmicand endoplasmic reticulum calcium ATPase (SERCA). Uptake of calcium intothe Golgi is mediated by a P-type calcium transport ATPase(PMR1/ATP2C1). Additionally, there is evidence that a significant amountof the calcium released upon IP₃ receptor activation is extruded fromthe cell through the action of the plasma membrane calcium ATPase. Forexample, plasma membrane calcium ATPases provide the dominant mechanismfor calcium clearance in human T cells and Jurkat cells, althoughsodium/calcium exchange also contributes to calcium clearance in human Tcells. Within calcium-storing organelles, calcium ions are bound tospecialized calcium-buffering proteins, such as, for example,calsequestrins, calreticulins and calnexins. Additionally, there arecalcium-buffering proteins in the cytosol that modulate calcium spikesand assist in redistribution of calcium ions. Thus, proteins and othermolecules that participate in any of these and other mechanisms throughwhich cytosolic calcium levels are reduced are proteins that areinvolved in, participate in and/or provide for cytoplasmic calciumbuffering. Thus, cytoplasmic calcium buffering allows for sustainedcalcium influx through SOC channels. Large increases in cytoplasmic Ca2+or store refilling deactivate SOCE.

Downstream Calcium Entry-Mediated Events

In addition to intracellular changes in calcium stores, store-operatedcalcium entry affects a multitude of events that are consequent to or inaddition to the store-operated changes. For example Ca²⁺ influx resultsin the activation of a large number of calmodulin-dependent enzymesincluding the serine phosphatase calcineurin. Activation of calcineurinby an increase in intracellular calcium results in acute secretoryprocesses such as mast cell degranulation. Activated mast cells releasepreformed granules containing histamine, heparin, TNFα and enzymes suchas β-hexosaminidase. Some cellular events, such as B and T cellproliferation, require sustained calcineurin signaling, which requires asustained increase in intracellular calcium. A number of transcriptionfactors are regulated by calcineurin, including NFAT (nuclear factor ofactivated T cells), MEF2 and NFκB. NFAT transcription factors playimportant roles in many cell types, including immune cells. In immunecells NFAT mediates transcription of a large number of molecules,including cytokines, chemokines and cell surface receptors.Transcriptional elements for NFAT have been found within the promotersof cytokines such as IL-2, IL-3, IL-4, IL-5, IL-8, IL-13, as well astumor necrosis factor alpha (TNFα), granulocyte colony-stimulatingfactor (G-CSF), and gamma-interferon (γ-IFN).

The activity of NFAT proteins is regulated by their phosphorylationlevel, which in turn is regulated by both calcineurin and NFAT kinases.Activation of calcineurin by an increase in intracellular calcium levelsresults in dephosphorylation of NFAT and entry into the nucleus.Rephosphorylation of NFAT masks the nuclear localization sequence ofNFAT and prevents its entry into the nucleus. Because of its strongdependence on calcineurin-mediated dephosphorylation for localizationand activity, NFAT is a sensitive indicator of intracellular calciumlevels.

Diseases, Disorders or Conditions

Clinical studies demonstrate that the CRAC channel is required for theactivation of genes underlying the T cell response to antigen. Sustainedcalcium entry is needed for lymphocyte activation and adaptive immuneresponse. Calcium entry into lymphocytes occurs primarily through theCRAC channels. Increased calcium leads to NFAT activation and expressionof cytokines required for immune response Inhibiting the store operatedcalcium entry is an efficient way to prevent T cell activation.

Inhibition of CRAC channel activity with the compounds described herein,such as compounds of Formula (I)-(XV) and Group A, provide a means forproviding immunosuppresive therapy as demonstrated by the elimination ofstore-operated calcium entry noted in patients with severe-combinedimmunodeficiency (SCID). T cells, fibroblasts, and in some cases Bcells, from patients with T cell immunodeficiency or SCID having aprincipal defect in T cell activation show a strong defect instore-operated calcium entry. SCID patients lack adaptive immuneresponse, but without any impairment or toxicity in major organs. TheSCID patient phenotype indicates that inhibition of CRAC channels is aneffective strategy for immunosuppression.

Diseases/Disorders Involving Inflammation and Diseases/Disorders Relatedto the Immune System

In some embodiments, diseases, disorders or conditions that are treatedor prevented using the compounds, compositions, and methods providedherein include diseases, conditions or disorders involving inflammationand/or that are related to the immune system. These diseases include butare not limited to asthma, chronic obstructive pulmonary disease,rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis,neuroinflammatory diseases such as multiple sclerosis, and disorders ofthe immune system.

The activation of neutrophils (PMN) by inflammatory mediators is partlyachieved by increasing cytosolic calcium concentration. Store-operatedcalcium influx in particular is thought to play an important role in PMNactivation. It has been shown that trauma increases PMN store-operatedcalcium influx and that prolonged elevations of cytosolic calciumconcentration due to enhanced store-operated calcium influx may alterstimulus-response coupling to chemotaxins and contribute to PMNdysfunction after injury. Modulation of PMN cytosolic calciumconcentration through store-operated calcium channels might therefore beuseful in regulating PMN-mediated inflammation and spare cardiovascularfunction after injury, shock or sepsis.

Calcium plays a critical role in lymphocyte activation. Activation oflymphocytes, e.g., by antigen stimulation, results in rapid increases inintracellular free calcium concentrations and activation oftranscription factors, including nuclear factor of activated T cells(NFAT), NF-κB, JNK1, MEF2 and CREB. NFAT is a key transcriptionalregulator of the IL-2 (and other cytokine) genes. A sustained elevationof intracellular calcium level is required to keep NFAT in atranscriptionally active state, and is dependent on store-operatedcalcium entry. Reduction or blocking of store-operated calcium entry inlymphocytes blocks calcium-dependent lymphocyte activation. Thus, insome embodiments, modulation of intracellular calcium, and particularlystore-operated calcium entry (e.g., reduction in, elimination ofstore-operated calcium entry), in lymphocytes is a method for treatingimmune and immune-related disorders, including, for example, chronicimmune diseases/disorders, acute immune diseases/disorders, autoimmuneand immunodeficiency diseases/disorders, diseases/disorders involvinginflammation, organ transplant graft rejections and graft-versus-hostdisease and altered (e.g., hyperactive) immune responses. For example,in some embodiments treatment of an automimmune disease/disorderinvolves reducing, blocking or eliminating store-operated calcium entryin lymphocytes.

Examples of immune disorders include psoriasis, rheumatoid arthritis,vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis,asthma, inflammatory muscle disease, allergic rhinitis, vaginitis,interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic orxenogeneic transplantation (organ, bone marrow, stem cells and othercells and tissues) graft rejection, graft-versus-host disease, lupuserythematosus, inflammatory disease, type I diabetes, pulmonaryfibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g.,Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmunehemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsinghepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopicdermatitis.

Cancer and Other Proliferative Diseases

In other embodiments, compounds of Formula (I)-(XV) and Group A,compositions thereof, and methods provided herein are used in connectionwith treatment of malignancies, including, but not limited to,malignancies of lymphoreticular origin, bladder cancer, breast cancer,colon cancer, endometrial cancer, head and neck cancer, lung cancer,melanoma, ovarian cancer, prostate cancer and rectal cancer.Store-operated calcium entry is thought to play an important role incell proliferation in cancer cells.

Inhibition of SOCE is sufficient to prevent tumor cell proliferation.The pyrazole derivative BTP-2, a direct I_(CRAC) blocker inhibits SOCEand proliferation in Jurkat cells and in colon cancer cells. It has beensuggested that sustained SOCE requires mitochonrial Ca²⁺ uptake and thatprevention of mitochondrial Ca²⁺ uptake leads to SOCE inhibition.Stimulation of Jurkat cells induces sustained SOCE and activation of theCa²⁺-dependent phosphatase calcineurin that dephosphorylates NFAT,promoting expression of interleukin-2 and proliferation. In otherembodiments, compounds of Formula (I)-(XV) and Group A inhibit SOCE andare used in the treatment of cancer or other proliferative diseases orconditions.

Liver Diseases and Disorders

In some embodiments, diseases, disorders or conditions that are treatedor prevented using the compounds of Formula (I)-(XV) and Group A,compositions thereof, and methods provided herein include hepatic orliver diseases and disorders. These diseases, conditions or disordersinclude but are not limited to liver injury, for example, due totransplantation, hepatitis and cirrhosis.

Store-operated calcium entry has been implicated in chronic liverdisease as well as transplantation injury after cold preservation-warmreoxygenation.

Kidney Diseases and Disorders

In some embodiments, diseases, conditions or disorders that are treatedor prevented using the methods provided herein include kidney or renaldiseases and disorders. Mesangial cell hyperplasia is often a keyfeature of such diseases and disorders. In other embodiments, suchdiseases and disorders are caused by immunological or other mechanismsof injury, including IgAN, membranoproliferative glomerulonephritis orlupus nephritis. Imbalances in the control of mesangial cell replicationalso appear to play a key role in the pathogenesis of progressive renalfailure.

The turnover of mesangial cells in normal adult kidney is very low witha renewal rate of less than 1%. A prominent feature of glomerular/kidneydiseases is mesangial hyperplasia due to elevated proliferation rate orreduced cell loss of mesangial cells. When mesangial cell proliferationis induced without cell loss, for example due to mitogenic stimulation,mesangioproliferative glomerulonephritis can result. Data have indicatedthat regulators of mesangial cell growth, particularly growth factors,are thought to act by regulating store-operated calcium channels. In yetother embodiments, modulators of store-operated calcium influx aids inthe treatment of glomerular diseases by inhibiting mesangial cellproliferation.

Store Operated Calcium Channels

Clinical studies demonstrate that the CRAC channel, a type of SOCchannel, is required for the activation of genes underlying the T cellresponse to antigen (Partiseti et al., J Biol. Chem., 269, 32327-32335,1994; Feske et al., Curr. Biol. 15, 1235-1241, 2005). In someembodiments, SOCE contributes directly to the elevation of cytosolicCa²⁺ levels ([Ca²⁺]_(i)), as in T lymphocytes where CRAC channelsgenerate the sustained Ca²⁺ signals needed to drive gene expressionunderlying T cell activation by antigen. Sustained calcium entry isneeded for lymphocyte activation and adaptive immune response. Calciumentry into lymphocytes occurs primarily through the CRAC channels.Increased calcium levels lead to NFAT activation and expression ofcytokines required for immune response.

The CRAC channel has a distinctive biophysical fingerprint, quantifiablestore-dependence, and essential function in T cells. Studies have shownthat CRAC channels are formed from two component proteins, whichinteract to form CRAC channels. The CRAC channel is assembled by twofunctional components, STIM1 and Orai1. STIM1 (stromal interactionmolecule 1) was identified as the mammalian ER Ca²⁺ sensor. Orai1/CRACM1was identified as a component of the mammalian CRAC channel.

STIM1 is the sensor of Ca²⁺ within ER Ca²⁺ stores, moving in response tostore depletion into ER puncta close to the plasma membrane. Orai1 is apore forming CRAC channel subunit in the plasma membrane. The twomembrane proteins STIM1 and Orai1 have each been shown to be essentialfor the activation of CRAC channels.

Expression of both STIM1 and Orai1 in human embryonic kidney 293 cells(HEK293 cells) reconstitute functional CRAC channels. Expression ofOrai1 alone strongly reduces store-operated Ca²⁺ entry in HEK293 cellsand the Ca²⁺ release-activated Ca²⁺ current (I_(CRAC)) in rat basophilicleukemia cells. However, expressed along with the store-sensing STIM1protein, Orai1 causes a massive increase in SOCE, enhancing the rate ofCa²⁺ entry by up to 103-fold. This entry is entirely store dependentsince the same coexpression causes no measurable store-independent Ca²⁺entry. The entry is completely blocked by the store operated channelblocker, 2-aminoethoxydiphenylborate. STIM proteins are known to mediateCa²⁺ store-sensing and endoplasmic reticulum-plasma membrane couplingwith no intrinsic channel properties. Orai1 contributes the plasmamembrane channel component responsible for Ca²⁺ entry. The suppressionof CRAC channel function by Orai1 overexpression reflects a requiredstoichiometry between STIM1 and Orai1.

Stromal Interacting Molecule (STIM) Proteins

In RNAi screen in Drosophila S2 cells using thapsigargin-activated Ca²⁺entry as a marker for store-operated channels, one gene gave asubstantially reduced Ca²⁺ entry, coding for the protein stromalinteraction molecule (Stim). There are two homologues of Stim inmammalian cells, STIM1 and STIM2, both of which appear to be distributedubiquitously. STIM1 is the ER Ca²⁺ sensor for store-operated Ca²⁺ entry.STIM1 is a 77 kDa type I membrane protein with multiple predictedprotein interaction or signaling domains and is located predominantly inthe ER, but also to a limited extent in the plasma membrane.

Knockdown of STIM1 by RNAi substantially reduced I_(CRAC) in Jurkat Tcells, and store-operated Ca²⁺ entry in HEK293 epithelial cells andSH-SY5Y neuroblastoma cells. However, knockdown of the closely relatedSTIM2 had no effect. These results indicate an essential role of STIM(Drosophila) and STIM1 (mammals) in the mechanism of activation ofstore-operated channels. It is unlikely that STIM1 is the store-operatedchannel itself. It has no channel-like sequence, and overexpression ofthe protein only modestly enhances Ca²⁺ entry. STIM1 is located both onthe plasma and intracellular membranes, such as the ER. The proteinsequence suggests that it spans the membrane once, with its NH₂ terminusoriented toward the lumen of the ER or the extracellular space. The NH₂terminus contains an EF-hand domain, and functions as the Ca²⁺ sensor inthe ER. The protein also contains protein-protein interaction domains,notably coiled-coiled domains in the cytoplasm and a sterile motif (SAM)in the ER (or extracellular space), both near the predictedtransmembrane domain. STIM1 can oligomerize and thus the protein in theER and plasma membrane could interact bridging the two.

Total internal reflection fluorescence (TIRF) and confocal microscopyreveal that STIM1 is distributed throughout the ER when Ca²⁺ stores arefull, but redistributes into discrete puncta near the plasma membrane onstore depletion. Although the redistribution of STIM1 into junctional ERregions is slow, it does precede the opening of CRAC channels by severaland is therefore rapid enough to be an essential step in the activationof CRAC channels.

It has been suggested that store depletion causes the insertion of STIM1into the plasma membrane where it may control store operated calciumentry through the CRAC channels.

Evidence for STIM1 as the Ca²⁺ sensor for SOCE is that mutation ofpredicted Ca²⁺-binding residues of the EF hand structural motif,expected to reduce its affinity for Ca²⁺ and hence mimic thestore-depleted state, causes STIM1 to redistribute spontaneously intopuncta and trigger constitutive Ca²⁺ influx through SOCs even whenstores are full.

Orai Proteins

Orai1 (also known as CRACM1) is a widely expressed, 33 kDa plasmamembrane protein with 4 transmembrane domains and a lack of significantsequence homology to other ion channels.

Studies of T cells from human patients with a severe combinedimmunodeficiency (SCID) syndrome, in which T cell receptor engagement orstore depletion failed to activate Ca²⁺ entry, was shown to be due to asingle point mutation in Orai1.

Other mammalian Orai homologues exist, e.g. Orai2 and Orai3, howevertheir function is not clearly defined. Orai2 and Orai3 can exhibit SOCchannel activity when overexpressed with STIM1 in HEK cells.

Evidence that Orai1 contributes to the CRAC channel pore was obtained byOrai1 mutagenesis studies. Selectivity of the CRAC channel for Ca²⁺ ionswas shown by mutations at either Glu 106 or Glu 190, which weaken theability of Ca²⁺ binding in order block permeation of monovalent cations(similar to mechanisms described for voltage-gated Ca²⁺ channels).

Neutralizing the charge on a pair of aspartates in the I-II loop (Asp110 and Asp 112) reduces block by Gd³⁺ and block of outward current byextracellular Ca²⁺, indicating that these negatively charged sites maypromote accumulation of polyvalent cations near the mouth of the pore.

Currents observed through overexpression of Orai1 closely resembleI_(CRAC), and the fact that Orai1 can form multimers, it is likely thatthe native CRAC channel is either a multimer of Orai1 alone or incombination with the closely related subunits Orai2 and/or Orai3.

Functional Store Operated Calcium Channels

The characterization of SOC channels has been largely obtained by onetype of SOC channel, the CRAC channel. CRAC channel activity istriggered by the loss of Ca²⁺ from the ER lumen, which is coupled to theopening of CRAC channels in the plasma membrane through the actions ofSTIM1 and Orai1. Depletion of Ca²⁺ is sensed by STIM1, causing it toaccumulate in junctional ER adjacent to the plasma membrane. In aTIRF-based Ca²⁺-imaging study to map the locations of open CRACchannels, [Ca²⁺]_(i) elevations were seen to co-localize with STIM1puncta, showing directly that CRAC channels open only in extremeproximity to these sites.

In cells co-expressing both STIM1 and Orai1, store depletion causesOrai1 itself to move from a dispersed distribution to accumulate in theplasma membrane directly opposite STIM1, enabling STIM1 to activate thechannel. Thus, CRAC channels are formed by apposed clusters of STIM1 inthe ER and Orai1 in the plasma membrane, separated by a narrow gap ofcytosol. The junctional gap (about 10-25 nm) may be small enough topermit protein-protein interactions. This is supported by the fact thatoverexpressed STIM1 and Orai1 can be co-immunoprecipitated.

Thus, STIM1 and Orai1 interact either directly or as members of amultiprotein complex. Support for this was observed when the expressionof the cytosolic portion of STIM1 by itself was sufficient to activateCRAC channels in one study, and the effects of deleting theERM/coiled-coil and other C-terminal domains suggest roles in STIM1clustering and SOC channel activation. On the luminal side of STIM1, theisolated EF-SAM region forms dimers and higher-order multimers onremoval of Ca²⁺ in vitro, indicating that STIM1 oligomerization may bean early step in store operated calcium activation.

Compounds of Formula (I)-(XV) and Group A described herein modulateintracellular calcium, such as, inhibition or reduction of SOCE and/orI_(CRAC). In some embodiments, the modulation by compounds of Formula(I)-(XV) and Group A result from a variety of effects, such as, but notlimited to, binding to a protein, interaction with a protein, ormodulation of interactions, activities, levels or any physical,structural or other property of a protein involved in modulatingintracellular calcium (e.g. a STIM protein and/or Orai protein).

For example, methods for assessing binding or interaction of a testagent with a protein involved in modulating intracellular calciuminclude NMR, mass spectroscopy, fluorescence spectroscopy, scintillationproximity assays, surface plasmon resonance assays and others. Examplesof methods for assessing modulation of interactions, activities, levelsor any physical, structural or other property of a protein involved inmodulating intracellular calcium include, but are not limited to, FRETassays to assess effects on protein interactions, NMR, X-raycrystallography and circular dichroism to assess effects on proteininteractions and on physical and structural properties of a protein, andactivity assays suitable for assessing a particular activity of aprotein.

Monitoring or Assessing Effects on Intracellular Calcium

In some embodiments, monitoring or assessing the effect of a compound ofFormula (I)-(XV) and Group A on intracellular calcium in any of thescreening/identification methods described herein, a direct or indirectevaluation or measurement of cellular (including cytosolic andintracellular organelle or compartment) calcium and/or movement of ionsinto, within or out of a cell, organelle, calcium store or portionsthereof (e.g., a membrane) are conducted. A variety of methods aredescribed herein for evaluating calcium levels and ion movements orflux. The particular method used and the conditions employed depend onwhether a particular aspect of intracellular calcium is being monitoredor assessed. For example, in some embodiments described herein, reagentsand conditions are known, and are used, for specifically evaluatingstore-operated calcium entry, resting cytosolic calcium levels, calciumbuffering and calcium levels and uptake by or release from intracellularorganelles and calcium stores. In other embodiments, the effect of acompound of Formula (I)-(XV) and Group A on intracellular calcium ismonitored or assessed using, for example, a cell, an intracellularorganelle or calcium storage compartment, a membrane (including, e.g., adetached membrane patch or a lipid bilayer) or a cell-free assay system(e.g., outside-out membrane vesicle). Generally, some aspect ofintracellular calcium is monitored or assessed in the presence of testagent and compared to a control, e.g., intracellular calcium in theabsence of test agent.

Methods of Modulating Intracellular Calcium

In some embodiments, modulation of intracellular calcium is anyalteration or adjustment in intracellular calcium including but notlimited to alteration of calcium concentration or level in the cytoplasmand/or intracellular calcium storage organelles, e.g., endoplasmicreticulum, alteration in the movement of calcium into, out of and withina cell or intracellular calcium store or organelle, alteration in thelocation of calcium within a cell, and alteration of the kinetics, orother properties, of calcium fluxes into, out of and within cells. Insome embodiments, intracellular calcium modulation involves alterationor adjustment, e.g. reduction or inhibition, of store-operated calciumentry, cytosolic calcium buffering, calcium levels in or movement ofcalcium into, out of or within an intracellular calcium store ororganelle, and/or basal or resting cytosolic calcium levels. In someembodiments, modulation of intracellular calcium involves an alterationor adjustment in receptor-mediated ion (e.g., calcium) movement, secondmessenger-operated ion (e.g., calcium) movement, calcium influx into orefflux out of a cell, and/or ion (e.g., calcium) uptake into or releasefrom intracellular compartments, including, for example, endosomes andlysosomes.

In one aspect, compounds described herein modulate intracellularcalcium, such as but not limited to, modulation (e.g. reduction orinhibition) of SOC channel activity, such as inhibition of CRAC channelactivity (e.g. inhibition of I_(CRAC), inhibition of SOCE), in an immunesystem cell (e.g., a lymphocyte, white blood cell, T cell, B cell), afibroblast (or a cell derived from a fibroblast), or an epidermal,dermal or skin cell (e.g., a keratinocyte). In some embodiments, thestep of modulating one or more proteins involved in modulatingintracellular calcium (e.g. a STIM protein and/or Orai protein)involves, for example, reducing the level, expression of, an activityof, function of and/or molecular interactions of a protein. Forinstance, if a cell exhibits an increase in calcium levels or lack ofregulation of an aspect of intracellular calcium modulation, e.g.,store-operated calcium entry, then in other embodiments, modulatinginvolves reducing the level of, expression of, an activity or functionof, or a molecular interaction of a protein, e.g. a STIM protein and/orOrai protein.

Treatment Methods

Presented herein is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)-(XV)or Group A, as discussed herein, or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I):

wherein Y is an optionally substituted arylalkyl.

In another embodiment the arylalkyl is

In yet another embodiment R₄, R₅, R₆, R₇, and R₁₀ are independentlyselected from H, F, Cl, Br, I, —CN, —NO₂, —OH, CF₃, —OCF₃, —OR⁸,C₁-C₆alkyl, C₃-C₈cycloalkyl or C₁-C₆heteroalkyl.

In a further embodiment R₆ and R₇; or R₇ and R₁₀; or R₅ and R₆; or R₄and R₅; together with the carbon atoms to which they are attached form aheterocycloalkyl group having at least one O, NH, or S. In yet a furtherembodiment the heterocycloalkyl group has two O atoms. In one embodimentR₆ is F. In another embodiment R₄ or R₁₀ is CF₃. In yet anotherembodiment R₁ is H. In a further embodiment R₁ is C₁-C₆alkyl. In yet afurther embodiment R₁ is CH₃. In one embodiment R₂ is an optionallysubstituted arylalkyl. In another embodiment the optionally substitutedarylalkyl is arylC₁-C₆alkyl. In yet another embodiment thearylC₁-C₆alkyl is phenyl-CH₂—CH₂— or phenyl-CH₂—. In a furtherembodiment the phenyl-CH₂—CH₂— or phenyl-CH₂— is substituted with atleast one R₃ selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,—OR⁸, C₁-C₆alkyl, C₃-C₈cycloalkyl or C₁-C₆heteroalkyl. In yet a furtherR₃ is F, OCF₃, OCH₃, or Cl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)wherein L is C(O). In another embodiment is a compound of Formula (I)wherein L is a bond. In yet another embodiment L is C₁-C₆alkyl.

In a further embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(I) wherein X is aryl. In yet a further embodiment aryl is phenyl. Inone embodiment phenyl is substituted with at least one R₃ selected fromF, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR⁸, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, optionally substituted heteroaryl. In one embodimentthe phenyl group has the structure

wherein R₁₁, R₁₂, R₁₃, R₁₄, and R₁₅ are independently selected from H,F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR⁸, C₁-C₆alkyl,C₃-C₈cycloalkyl or C₁-C₆heteroalkyl. In another embodiment R₁₃ is OH. Inyet another embodiment R₁₃ is OCH₃. In a further embodiment R₁₃ is OCF₃.In yet a further embodiment R₁₁ and R₁₂; or R₁₂ and R₁₃; or R₁₃ and R₁₄;or R₁₄ and R₁₅; together with the carbon atoms to which they areattached form a heterocycloalkyl group having at least one O, NH, or S.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)wherein X is heteroaryl. In another embodiment heteroaryl is selectedfrom pyridine, pyrimidine, pyrazine, pyrazole, oxazole, thiazole,isoxazole, isothiazole, 1,3,4-oxadiazole, pyridazine, 1,3,5-trazine,1,2,4-triazine, quinoxaline, benzimidazole, benzotriazole, purine,1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole, imidazole, thiophene,furan, isobenzofuran, pyrrole, indolizine, isoindole, indole, indazole,isoquinoline, quinoline, phthalazine, naphthyridine, quinazoline,cinnoline, and pteridine. In yet another embodiment the heteroaryl isthiophene. In a further embodiment the heteroaryl is furan. In yet afurther embodiment wherein X is C₁-C₆alkyl. In one embodiment X is—CH(CH₂CH₃)₂. In another embodiment X is CH₂CH₃. In yet anotherembodiment X is t-butyl. In a further embodiment R₂ is heteroarylalkyl.In yet a further embodiment heteroarylalkyl is C₁-C₆-furan. In oneembodiment the heteroarylalkyl is CH₂-furan.

In another embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(I) wherein L is C₁-C₆alkenylene. In yet another embodimentC₁-C₆alkenylene is CH₂—CH═CH.

In one aspect is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)wherein the compound of Formula (I) is selected from the groupconsisting of:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In another embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(IV):

wherein X is aryl. In another embodiment the aryl is a phenyl group. Inone embodiment the phenyl group is substituted with at least one R₁selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl. In yetanother embodiment R₁ is CH₃. In a further embodiment R₁ is Cl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (IV)wherein X is heteroaryl. In another embodiment heteroaryl is selectedfrom thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl,xanthenyl, phenoxathiinyl, pyrrolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl,carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl,and phenoxazinyl. In yet another embodiment heteroaryl is substitutedwith at least one R₁ selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,—OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted aryl,optionally substituted O-aryl, and optionally substituted heteroaryl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (IV)wherein Y is aryl. In yet a further embodiment aryl is a phenyl group.In one embodiment the phenyl group is substituted with at least one R₃selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl. In anotherembodiment R₃ is monosubstituted. In yet another embodiment R₃ isdisubstituted. In a further embodiment R₃ is OR₉. In yet a furtherembodiment R₉ is C₁-C₆alkyl. In one embodiment C₁-C₆alkyl is selectedfrom methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl andtert-butyl. In another embodiment C₁-C₆alkyl is methyl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (IV)wherein Y is heteroaryl.

In a further embodiment heteroaryl is selected from thienyl,thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathiinyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, and phenoxazinyl.In yet a further embodiment heteroaryl is substituted with at least oneR₁ selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (IV)wherein Z is aryl. In another embodiment aryl is a phenyl group. In yetanother embodiment the phenyl group is substituted with at least one R₁selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl. In a furtherembodiment R₁ is monosubstituted. In yet a further embodiment R₁ isdisubstituted. In one embodiment R₁ is CF₃. In one embodiment R₁ isC₁-C₆alkyl. In another embodiment C₁-C₆alkyl is selected from methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl. In yetanother embodiment C₁-C₆alkyl is methyl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (IV)wherein Z is heteroaryl.

In yet a further embodiment heteroaryl is selected from thienyl,thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathiinyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, and phenoxazinyl.

In one embodiment heteroaryl is substituted with at least one R₁selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (IV)wherein the compound of Formula (IV) is selected from the groupconsisting of:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In another aspect, described herein is a method of modulatingstore-operated calcium (SOC) channel activity comprising contacting thestore operated calcium (SOC) channel complex, or portion thereof, with acompound of Formula (VI):

wherein R₁ is hydrogen or C₁-C₆alkyl. In another embodiment R₁ ishydrogen. In yet another embodiment R₁ is C₁-C₆alkyl. In a furtherembodiment C₁-C₆alkyl is selected from methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet a furtherembodiment C₁-C₆alkyl is ethyl. In one embodiment R₃ is hydrogen.

In another embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(VI) wherein Y is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,—OCF₃, —OR₈, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted aryl,optionally substituted O-aryl, and optionally substituted heteroaryl. Inyet another embodiment Y is selected from F, Cl, Br, and I. In a furtherembodiment Y is Cl. In yet a further embodiment Y is —N(R₉)(R₁₀). In oneembodiment R₉ is C₁-C₆alkyl.

In another embodiment C₁-C₆alkyl is selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yet anotherembodiment C₁-C₆alkyl is ethyl. In a further embodiment R₁₀ isC₁-C₆alkyl. In yet a further embodiment C₁-C₆alkyl is selected frommethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.In one embodiment C₁-C₆alkyl is ethyl. In another embodiment R₉ and R₁₀and the nitrogen atom to which they are attached form a 6 memberedheterocyclic ring. In a further embodiment C₁-C₆alkyl is selected frommethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.In yet a further embodiment C₁-C₆alkyl is methyl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (VI)wherein R₂ is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,—OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted aryl,optionally substituted O-aryl, and optionally substituted heteroaryl. Inanother embodiment R₂ is C₁-C₆alkyl. In yet another embodimentC₁-C₆alkyl is selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, and tert-butyl. In a further embodiment C₁-C₆alkylis methyl. In yet a further embodiment C₁-C₆alkyl is monosubstituted,disubstituted or trisubstituted. In one embodiment R₂ is OR₉. In anotherembodiment R₉ is C₁-C₆alkyl. In yet another embodiment C₁-C₆alkyl isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In a further embodiment C₁-C₆alkyl is methyl.

In yet a further embodiment is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store-operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (VI) wherein X is aryl. In one embodiment aryl is a phenylgroup. In another embodiment the phenyl group is substituted with atleast one R₂ selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,—OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl. In yetanother embodiment R₂ is OR₉. In a further embodiment R₉ is C₁-C₆alkyl.In yet a further embodiment C₁-C₆alkyl is selected from methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In oneembodiment C₁-C₆alkyl is methyl. In one embodiment the phenyl group issubstituted with —S(═O)₂N(R₉)₂. In another embodiment each R₉ isC₁-C₆alkyl. In yet another embodiment C₁-C₆alkyl is selected frommethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.In a further embodiment C₁-C₆alkyl is methyl. In yet a furtherembodiment aryl is naphthalene.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (VI)wherein X is 9H-xanthene. In another embodiment X is heterocycloalkyl.In yet another embodiment heterocycloalkyl is5,6-dihydro-4H-cyclopenta[b]thiophene. In a further embodiment X isarylheteroalkyl. In yet a further embodiment arylheteroalkyl isCH₂O-aryl. In one embodiment aryl is a phenyl group. In anotherembodiment the phenyl group is substituted with at least one R₂ selectedfrom F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl. In yetanother embodiment R₂ is C₁-C₆alkyl. In a further embodiment C₁-C₆alkylis selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, and tert-butyl. In yet a further embodiment C₁-C₆alkyl ismethyl.

In another embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(VI) wherein the compound of Formula (VI) is selected from the groupconsisting of:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofGroup A:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (VIII):

wherein R₁ is selected from F, Cl, Br, or I. In one embodiment R₁ is Cl.In another embodiment R₁ is C₁-C₆alkyl. In yet another embodimentC₁-C₆alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In a further embodiment C₁-C₆alkyl is methyl. In yet afurther embodiment R₂ is selected from F, Cl, Br, or I. In oneembodiment R₂ is Cl. In another embodiment R₂ is C₁-C₆alkyl. In yetanother embodiment C₁-C₆alkyl is methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, and tert-butyl. In yet a further embodimentC₁-C₆alkyl is methyl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (VIII)wherein X is —OC₁-C₆alkylaryl. In one embodiment C₁-C₆alkyl is CH₂,CH₂CH₂, or CH₂CH₂CH₂. In another embodiment C₁-C₆alkyl is CH₂. In yetanother embodiment aryl is a phenyl group. In a further embodiment thephenyl group is substituted with at least one R₃ selected from F, Cl,Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionallysubstituted aryl, optionally substituted O-aryl, and optionallysubstituted heteroaryl. In yet a further embodiment R₃ is OR₉. In oneembodiment R₉ is C₁-C₆alkyl. In another embodiment C₁-C₆alkyl is methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl. In yetanother embodiment C₁-C₆alkyl is methyl.

In a further embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(VIII) wherein X is —OR₄. In yet a further embodiment R₄ isC₁-C₆alkyl-C(═O)N(R₉)(R₁₀). In one embodiment C₁-C₆alkyl is CH₂, CH₂CH₂,or CH₂CH₂CH₂. In another embodiment C₁-C₆alkyl is CH₂. In yet anotherembodiment R₉ is independently selected from H or phenyl. In a furtherembodiment R₉ is phenyl. In yet a further embodiment phenyl issubstituted with at least one R₅ is selected from F, Cl, Br, I, —CN,—NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionallysubstituted aryl, optionally substituted O-aryl, and optionallysubstituted heteroaryl. In one embodiment R₅ is selected from F, Cl, Br,or I. In another embodiment R₅ is Cl. In yet another embodiment R₅ isCF₃. In a further embodiment R₅ is monosubstituted, disubstituted ortrisubstituted. In yet a further embodiment R₁₀ is H.

In a further embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(VIII) wherein the compound of Formula (VIII) is selected from the groupconsisting of:

or A pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (XI):

wherein X is aryl. In one embodiment aryl is a phenyl group. In anotherembodiment the phenyl group is substituted with at least one R₃ selectedfrom F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl. In yetanother embodiment R₃ is C₁-C₆alkyl. In a further embodiment C₁-C₆alkylis selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, and tert-butyl. In yet a further embodiment C₁-C₆alkyl ismethyl.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (XI)wherein X is heteroaryl. In another embodiment heteroaryl is selectedfrom thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl,xanthenyl, phenoxathiinyl, pyrrolyl, imidazolyl, pyrazolyl,isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzothiazolyl, indazolyl,purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,4aH-carbazolyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl.In one embodiment heteroaryl is thienyl. In yet another embodiment R₂ isH. In a further embodiment R₃ is aryl. In yet a further embodiment arylis a phenyl group. In one embodiment the phenyl group is substitutedwith at least one R₃ selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,—OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted aryl,optionally substituted O-aryl, and optionally substituted heteroaryl. Inanother embodiment R₃ is C₁-C₆alkyl. In yet another embodimentC₁-C₆alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,and tert-butyl. In a further embodiment C₁-C₆alkyl is n-butyl. In yet afurther embodiment R₃ is optionally substituted aryl. In one embodimentthe optionally substituted aryl is a phenyl group.

In another embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(XI) wherein R₃ is optionally substituted heteroaryl. In yet anotherembodiment optionally substituted heteroaryl is selected from thienyl,thianthrenyl, furyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathiinyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl,isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,isoindolyl, 3H-indolyl, indolyl, benzothiazolyl, indazolyl, purinyl,4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl,carbazolyl, carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl,and phenoxazinyl. In a further embodiment heteroaryl is benzothiazolyl.In yet a further embodiment benzothiazolyl is substituted with at leastone R₃ selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl, andC₂-C₈heterocycloalkyl. In one embodiment R₃ is OR₉. In anotherembodiment R₉ is C₁-C₆alkyl. In yet another embodiment C₁-C₆alkyl ismethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.In a further embodiment C₁-C₆alkyl is methyl.

In a further embodiment is a method of modulating store-operated calcium(SOC) channel activity comprising contacting the store-operated calcium(SOC) channel complex, or portion thereof, with a compound of Formula(XI) wherein the compound of Formula (XI) is selected from the groupconsisting of:

or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a method of modulating store-operatedcalcium (SOC) channel activity comprising contacting the store operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (XIV):

wherein X is aryl or heteroaryl. In one embodiment, X is aryl. Inanother embodiment aryl is phenyl.

In yet another embodiment phenyl is substituted with at least one R₃selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl. In oneembodiment, R₃ is selected from F, Cl, Br, and I. In another embodiment,R₃ is OR₉. In a further embodiment, R₉ is H. In a further embodiment,the aryl group is monosubstituted, disubstituted, or trisubstituted. Inyet a further embodiment, the aryl group is disubstituted with OR₉wherein R₉ is H.

In a further embodiment two R₃ together with the atoms to which they areattached form a heterocycloalkyl group having at least one O, NH, or S.In yet a further embodiment the heterocycloalkyl group has two O atoms.In another embodiment, two R₃ together with the atoms to which they areattached form a five-membered heterocycloalkyl group having two O atoms.In yet another embodiment, two R₃ together with the atoms to which theyare attached form a six-membered heterocycloalkyl group having two Oatoms.

In one embodiment X is heteroaryl. In another embodiment heteroaryl isselected from pyridine, pyrimidine, pyrazine, pyrazole, oxazole,thiazole, isoxazole, isothiazole, 1,3,4 oxadiazole, pyridazine,1,3,5-trazine, 1,2,4-triazine, quinoxaline, benzimidazole,benzotriazole, purine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole,imidazole, thiophene, furan, isobenzofuran, pyrrole, indolizine,isoindole, indole, indazole, isoquinoline, quinoline, phthalazine,naphthyridine, quinazoline, cinnoline, and pteridine. In yet anotherembodiment heteroaryl is substituted with at least one R₃ selected fromF, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, optionally substituted heteroaryl. In oneembodiment, R₃ is selected from F, Cl, Br, and I. In another embodiment,R₃ is OR₉. In a further embodiment, R₉ is H. In a further embodiment,the heteroaryl group is monosubstituted, disubstituted, ortrisubstituted. In yet a further embodiment, the heteroaryl group isdisubstituted with OR₉ wherein R₉ is H.

In a further embodiment Y is NR₂(C₁-C₆alkyl), O(C₁-C₆alkyl), andS(C₁-C₆alkyl). In yet a further embodiment Y is NR₂(C₁-C₆alkyl). In oneembodiment R₂ is H. In another embodiment C₁-C₆alkyl is CH₂, CH₂CH₂, andCH₂CH₂CH₂. In yet another embodiment C₁-C₆alkyl is CH₂CH₂. In oneembodiment, Y is a bond. In a further embodiment, Y is C₁-C₆alkyl. Inyet a further embodiment, C₁-C₆alkyl is CH₂, CH₂CH₂, or CH₂CH₂CH₂. In afurther embodiment, Y is NR₂(C₂-C₆alkenyl), O(C₂-C₆alkenyl), orS(C₂-C₆alkenyl). In a further embodiment, Y is NR₂(C₂-C₆alkenyl). In yeta further embodiment, C₂-C₆alkenyl is CH₂CHCH, CH₂CH₂CHCH. In a furtherembodiment, R₂ is H. In another embodiment, Y is NR₂(C₁-C₆alkyl),O(C₁-C₆alkyl), S(C₁-C₆alkyl) wherein C₁-C₆alkyl is optionallysubstituted with at least one group selected from F, Cl, Br, I, —CN,—NO₂, —OH, —CF₃, —OCF₃, —OR₉. In another embodiment, R₉ is H.

In a further embodiment Z is aryl or heteroaryl. In yet a furtherembodiment Z is aryl. In one embodiment aryl is phenyl. In anotherembodiment phenyl is substituted with at least one R₄ selected from F,Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, OCHF₂, —OR₉, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, optionally substituted heteroaryl. In yet anotherembodiment R₄ is selected from F, Cl, Br, and I. In a further embodimentR₄ is F. In yet a further embodiment, the aryl is monosubstituted,disubstituted, or trisubstituted. In another embodiment, Z isheteroaryl. In yet another embodiment, Z is a heteroaryl selected frompyridine, pyrimidine, pyrazine, pyrazole, oxazole, thiazole, isoxazole,isothiazole, 1,3,4-oxadiazole, pyridazine, 1,3,5-trazine,1,2,4-triazine, quinoxaline, benzimidazole, benzotriazole, purine,1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole, imidazole, thiophene,furan, isobenzofuran, pyrrole, indolizine, isoindole, indole, indazole,isoquinoline, quinoline, phthalazine, naphthyridine, quinazoline,cinnoline, and pteridine. In yet another embodiment the heteroaryl issubstituted with at least one R₄ selected from F, Cl, Br, I, —CN, —NO₂,—OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted aryl,optionally substituted O-aryl, optionally substituted heteroaryl. In oneembodiment, R₄ is selected from F, Cl, Br, and I. In another embodiment,R₄ is OR₉. In a further embodiment, R₉ is H. In a further embodiment,the heteroaryl group is monosubstituted, disubstituted, ortrisubstituted. In yet a further embodiment, the heteroaryl group isdisubstituted with OR₉ wherein R₉ is H.

In yet a further embodiment each R₁ is independently H. In anotherembodiment, R₁ is selected from F, Cl, Br, and I.

In one embodiment is a method of modulating store-operated calcium (SOC)channel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (XIV)wherein the compound of Formula (XIV) is:

or a pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a method of modulating store-operated calciumchannel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)-(XV)or Group A, wherein the contacting occurs in vitro.

In another embodiment is a method of modulating store-operated calciumchannel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)-(XV)or Group A, wherein the contacting occurs in vivo.

In yet another embodiment is a method of modulating store-operatedcalcium channel activity comprising contacting the store-operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (I)-(XV) or Group A, wherein the compound of Formula (I)-(XV) orGroup A modulates an activity of, modulates an interaction of, ormodulates the level of, or binds to, or interacts with at least oneportion of the store operated calcium channel complex selected fromstromal interaction molecules (STIM) family of proteins.

In a further embodiment is a method of modulating store-operated calciumchannel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)-(XV)or Group A, wherein the compound of Formula (I)-(XV) or Group Amodulates an activity of, modulates an interaction of, or modulates thelevel of, or binds to, or interacts with at least one portion of STIM1or STIM2.

In another embodiment is a method of modulating store-operated calciumchannel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)-(XV)or Group A, wherein modulating store operated calcium channel activitywith a compound of Formula (I)-(XV) or Group A inhibits store-operatedcalcium entry (SOCE).

In yet another embodiment is a method of modulating store-operatedcalcium channel activity comprising contacting the store-operatedcalcium (SOC) channel complex, or portion thereof, with a compound ofFormula (I)-(XV) or Group A, wherein the store operated calcium channelcomplex is calcium-release activated calcium (CRAC) channel complex.

In a further embodiment is a method of modulating store-operated calciumchannel activity comprising contacting the store-operated calcium (SOC)channel complex, or portion thereof, with a compound of Formula (I)-(XV)or Group A, wherein modulating calcium release activated calcium (CRAC)activity with a compound of Formula (I)-(XV) or Group A inhibits theelectrophysiological current (I_(CRAC)) directly associated withactivated CRAC channels.

Also presented herein is a method of modulating calcium releaseactivated calcium channel (CRAC) activity in a mammal comprisingadministering a compound of Formula (I)-(XV) or Group A, orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof.

In one embodiment is a method of modulating calcium release activatedcalcium channel (CRAC) activity in a mammal comprising administering acompound of Formula (I)-(XV) or Group A, or pharmaceutically acceptablesalt, pharmaceutically acceptable solvate, or pharmaceuticallyacceptable prodrug thereof wherein the compound of Formula (I)-(XV) orGroup A modulates an activity of, modulates an interaction of, ormodulates the level of, or binds to, or interacts with at least onecomponent of the calcium release activated (CRAC) channel complexselected from stromal interaction molecules (STIM) family of proteins.

In another embodiment is a method of modulating calcium releaseactivated calcium channel (CRAC) activity in a mammal comprisingadministering a compound of Formula (I)-(XV) or Group A, orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof wherein the compound ofFormula (I)-(XV) or Group A modulates an activity of, modulates aninteraction of, or modulates the level of, or binds to, or interactswith STIM1 or STIM2.

In yet another embodiment is a method of modulating calcium releaseactivated calcium channel (CRAC) activity in a mammal comprisingadministering a compound of Formula (I)-(XV) or Group A, orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof wherein modulatingcalcium release activated calcium (CRAC) channel activity with acompound of Formula (I)-(XV) or Group A inhibits store-operated calciumentry (SOCE).

In a further embodiment is a method of modulating calcium releaseactivated calcium channel (CRAC) activity in a mammal comprisingadministering a compound of Formula (I)-(XV) or Group A, orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof wherein modulatingcalcium release activated calcium (CRAC) channel activity with acompound of Formula (I)-(XV) or Group A inhibits theelectrophysiological current (I_(CRAC)) directly associated withactivated CRAC channels.

In yet a further embodiment is a method of modulating calcium releaseactivated calcium channel (CRAC) activity in a mammal comprisingadministering a compound of Formula (I)-(XV) or Group A, orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof wherein the compound ofFormula (I)-(XV) or Group A inhibits SOCE with an IC₅₀ below 10 μM.

In another embodiment is a method of modulating calcium releaseactivated calcium channel (CRAC) activity in a mammal comprisingadministering a compound of Formula (I)-(XV) or Group A, orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof wherein the compound ofFormula (I)-(XV) or Group A inhibits electrophysiological current(I_(CRAC)) directly associated with activated CRAC channels at aconcentration below 10 μM.

In one aspect is a method of treating a disease, disorder or conditionin a mammal that would benefit from inhibition of store operated calciumchannel activity comprising administering to the mammal a compound ofFormula (I)-(XV) or Group A, or pharmaceutically acceptable salt,pharmaceutically acceptable solvate, or pharmaceutically acceptableprodrug thereof.

In one embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof wherein the compound ofFormula (I)-(XV) or Group A modulates the activity of, modulates aninteraction of, or binds to, or interacts with a mammalian STIM1protein, or a mammalian STIM2 protein.

In another embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof wherein the disease,disorder or condition in a mammal is selected from diseases/disordersinvolving inflammation, glomerulonephritis, uveitis, hepatic diseases ordisorders, renal diseases or disorders, chronic obstructive pulmonarydisease, rheumatoid arthritis, psoriasis, inflammatory bowel disease,vasculitis, dermatitis, osteoarthritis, inflammatory muscle disease,allergic rhinitis, vaginitis, interstitial cystitis, scleroderma,osteoporosis, eczema, organ transplant rejection, allogeneic orxenogeneic transplantation, graft rejection, graft-versus-host disease,lupus erythematosus, type I diabetes, pulmonary fibrosis,dermatomyositis, thyroiditis, myasthenia gravis, autoimmune hemolyticanemia, cystic fibrosis, chronic relapsing hepatitis, primary biliarycirrhosis, allergic conjunctivitis, hepatitis and atopic dermatitis,asthma, multiple sclerosis, Sjogren's syndrome, and autoimmune diseasesor disorders.

In yet another embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof wherein the disease,disorder or condition is rheumatoid arthritis.

In a further embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof wherein the disease,disorder or condition is psoriasis.

In one embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof wherein the disease,disorder or condition is inflammatory bowel disease.

In a further embodiment the inflammatory bowel disease is ulcerativecolitis.

In a further embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof wherein the disease,disorder or condition is organ transplant rejection.

In a further embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof wherein the disease,disorder or condition is multiple sclerosis.

In yet a further embodiment is a method of treating a disease, disorderor condition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof further comprisingadministering to the mammal a second therapeutic agent.

In another embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof, wherein the secondtherapeutic agent is selected from immunosuppressants, glucocorticoids,non-steroidal anti-inflammatory drugs, Cox-2-specific inhibitors,leflunomide, gold thioglucose, gold thiomalate, aurofin, sulfasalazine,hydroxychloroquinine, minocycline, anti-TNF-α agents, abatacept,anakinra, interferon-β, interferon-γ, interleukin-2, allergy vaccines,antihistamines, antileukotrienes, beta-agonists, theophylline, andanticholinergics.

In yet another embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from inhibition of storeoperated calcium channel activity comprising administering to the mammala compound of Formula (I)-(XV) or Group A, or pharmaceuticallyacceptable salt, pharmaceutically acceptable solvate, orpharmaceutically acceptable prodrug thereof, wherein the secondtherapeutic agent is selected from tacrolimus, cyclosporin, rapamicin,methotrexate , cyclophosphamide, azathioprine, mercaptopurine,mycophenolate, or FTY720, prednisone, cortisone acetate, prednisolone,methylprednisolone, dexamethasone, betamethasone, triamcinolone,beclometasone, fludrocortisone acetate, deoxycorticosterone acetate,aldosterone, aspirin, salicylic acid, gentisic acid, choline magnesiumsalicylate, choline salicylate, choline magnesium salicylate, cholinesalicylate, magnesium salicylate, sodium salicylate, diflunisal,carprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen,ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen,oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin,meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam,meloxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,lumiracoxib, CS-502, JTE-522, L-745,337 and NS398, leflunomide, goldthioglucose, gold thiomalate, aurofin, sulfasalazine,hydroxychloroquinine, minocycline, infliximab, etanercept, adalimumab,abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergyvaccines, antihistamines, antileukotrienes, beta-agonists, theophylline,and anticholinergics.

Also described herein is a method of inhibiting store-operated calciumentry (SOCE) activation of nuclear factor of activated T cells (NFAT) ina mammal comprising administering a compound of Formula (I)-(XV) orGroup A, or pharmaceutically acceptable salt, pharmaceuticallyacceptable solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a method of inhibiting store-operated calcium entry(SOCE) activation of nuclear factor of activated T cells (NFAT) in amammal comprising administering a compound of Formula (I)-(XV) or GroupA, or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof, wherein thecompound of Formula (I)-(XV) or Group A modulates an interaction of, ormodulates the level of, or binds to, or interacts with a mammalian STIM1protein, or a mammalian STIM2 protein.

In another aspect is a method of decreasing cytokine expression byinhibiting the store-operated calcium entry activation of NFAT in amammal comprising administering a compound of Formula (I)-(XV) or GroupA, or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof.

In another embodiment is a method of decreasing cytokine expression byinhibiting the store-operated calcium entry activation of NFAT in amammal comprising administering a compound of Formula (I)-(XV) or GroupA, or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof wherein thecompound of Formula (I)-(XV) or Group A modulates an interaction of, ormodulates the level of, or binds to, or interacts with a mammalian STIM1protein or a mammalian STIM2 protein.

In yet another embodiment is a method of decreasing cytokine expressionby inhibiting the store-operated calcium entry activation of NFAT in amammal comprising administering a compound of Formula (I)-(XV) or GroupA, or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof wherein thecytokine is selected from IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17, IL-18, IL-1α,IL-1β, IL-1 RA, granulocyte colony stimulating factor (G-CSF),granulocyte-macrophage colony stimulating factor (GM-CSF), oncostatin M,erythropoietin, leukemia inhibitory factor (LIF), interferons,gamma-interferon (γ-IFN), B7.1 (CD80), B7.2 (B70, CD86), TNF-α, TNF-β,LT-β, CD40 ligand, Fas ligand, CD27 ligand, CD30 ligand, 4-1BBL, Trail,and migration inhibitory factor (MIF).

Compounds

Compounds described herein modulate intracellular calcium and are usedin the treatment of diseases, disorders or conditions where modulationof intracellular calcium has a beneficial effect. In one embodiment,compounds described herein inhibit store operated calcium entry. In oneembodiment, compounds of Formula (I)-(XV) and Group A interrupt theassembly of SOCE units. In another embodiment, compounds of Formula(I)-(XV) and Group A alter the functional interactions of proteins thatform store operated calcium channel complexes. In one embodiment,compounds of Formula (I)-(XV) and Group A alter the functionalinteractions of STIM1 with Orai1. In other embodiments, compounds ofFormula (I) are SOC channel pore blockers. In other embodiments,compounds of Formula (I)-(XV) and Group A are CRAC channel poreblockers.

In one aspect, compounds of Formula (I)-(XV) and Group A inhibit theelectrophysiological current (I_(SOC)) directly associated withactivated SOC channels. In one aspect, compounds of Formula (I)-(XV) andGroup A inhibit the electrophysiological current (I_(CRAC)) directlyassociated with activated CRAC channels.

In other embodiments, the diseases, conditions or disorders that benefitfrom modulation of intracellular calcium include, but are not limitedto, an immune system-related disease (e.g., an autoimmune disease), adisease or disorder involving inflammation (e.g., asthma, chronicobstructive pulmonary disease, rheumatoid arthritis, inflammatory boweldisease, glomerulonephritis, neuroinflammatory diseases, multiplesclerosis, and disorders of the immune system), cancer or otherproliferative disease, kidney disease and liver disease. In oneembodiment, compounds described herein are used as immunosuppressants toprevent transplant graft rejections, allogeneic or xenogeneictransplantation rejection (organ, bone marrow, stem cells, other cellsand tissues), graft-versus-host disease. In other embodiments,transplant graft rejections result from tissue or organ transplants. Infurther embodiments, graft-versus-host disease results from bone marrowor stem cell transplantation.

Compounds described herein modulate an activity of, modulate aninteraction of, or binds to, or interacts with at least one portion of aprotein in the store operated calcium channel complex. In oneembodiment, compounds described herein modulate an activity of, modulatean interaction of, or binds to, or interacts with at least one portionof a protein in the calcium release activated calcium channel complex.In one embodiment, compounds described herein reduce the level offunctional store operated calcium channel complexes. In one embodiment,compounds described herein reduce the level of activated store operatedcalcium channel complexes. In one embodiment, store operated calciumchannel complexes are calcium release activated calcium channelcomplexes.

Compounds described herein for treatment of a disease or disorder, whenadministered to a subject having a disease or disorder effectivelyreduces, ameliorates or eliminates a symptom or manifestation of thedisease, condition or disorder. In other embodiments, compoundsdescribed herein also are administered to a subject predisposed to adisease, condition or disorder that does not yet manifest a symptom ofthe disease, condition or disorder, prevents or delays development ofthe symptoms. In further embodiments, the agent has such effects aloneor in combination with other agents, or functions to enhance atherapeutic effect of another agent.

In some embodiments, the compounds described herein, pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, orpharmaceutically acceptable solvates thereof, modulate intracellularcalcium, and are used to treat patients where modulation ofintracellular calcium provides benefit.

In one aspect, described herein is a compound of Formula (II):

wherein:

-   -   L is a bond, C₁-C₆alkyl, C₁-C₆alkenylene, heteroalkyl;    -   X is aryl or heteroaryl; wherein aryl or heteroaryl is        optionally substituted with at least one R₃;    -   R₁ is selected from H, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₃-C₈cycloalkyl, phenyl, and benzyl;    -   R₂ is aryl, arylalkyl, heteroaryl, heteroarylalkyl; wherein the        aryl, arylalkyl, heteroaryl, heteroarylalkyl is optionally        substituted with at least one R₃;    -   R₄ and R₁₀ are each independently selected from H, F, Cl, Br, I,        —CN, —NO₂, —OH, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₆ is selected from H, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₃, R₅ and R₇ are each independently selected from H, F, Cl, Br,        I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or    -   a pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (II) wherein L is a bond. Inanother embodiment is a compound of Formula (II) wherein L isheteroalkyl. In yet another embodiment is a compound of Formula (II)wherein heteroalkyl is CH₂—O. In a further embodiment is a compound ofFormula (II) wherein X is aryl. In yet a further embodiment is acompound of Formula (II) wherein aryl is a phenyl group. In oneembodiment is a compound of Formula (II) wherein the phenyl group issubstituted with at least one R₃ selected from F, Cl, Br, I, —CN, —NO₂,—OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted aryl,optionally substituted O-aryl, and optionally substituted heteroaryl. Inyet another embodiment is a compound of Formula (II) wherein R₁ ishydrogen. In another embodiment is a compound of Formula (II) wherein R₂is aryl. In a further embodiment is a compound of Formula (II) whereinaryl is a phenyl group. In yet a further embodiment is a compound ofFormula (II) wherein R₂ is arylalkyl. In one embodiment is a compound ofFormula (II) wherein arylalkyl is CH₂-phenyl.

In another aspect is a compound of Formula (III):

wherein:

-   -   L and L₁ are each independently a bond, C₁-C₆alkyl,        C₁-C₆alkenylene, heteroalkyl;    -   X and X₁ are each independently aryl or heteroaryl; wherein aryl        or heteroaryl is optionally substituted with at least one R₃;    -   R₁ is selected from H, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₃-C₈cycloalkyl, phenyl, and benzyl;    -   R₄ and R₁₀ are each independently selected from H, F, Cl, Br, I,        —CN, —NO₂, —OH, CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₆ is selected from H, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₃, R₅ and R₇ are each independently selected from H, F, Cl, Br,        I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or    -   a pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (III) wherein L isC₁-C₆alkyl.

In another embodiment is a compound of Formula (III) wherein L isC₁-C₆alkenylene.

In yet another embodiment is a compound of Formula (III) wherein L₁ isC₁-C₆alkyl.

In a further embodiment is a compound of Formula (III) wherein L₁ isC₁-C₆alkenylene.

In yet a further embodiment is a compound of Formula (III) wherein X isaryl.

In one embodiment is a compound of Formula (III) wherein X isheteroaryl.

In another embodiment is a compound of Formula (III) wherein aryl is aphenyl group.

In yet another embodiment is a compound of Formula (III) wherein thephenyl group is substituted with at least one R₃ selected from F, Cl,Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionallysubstituted aryl, optionally substituted O-aryl, and optionallysubstituted heteroaryl.

In a further embodiment is a compound of Formula (III) wherein theheteroaryl is selected from pyridine, pyrimidine, pyrazine, pyrazole,oxazole, thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, pyridazine,1,3,5-trazine, 1,2,4-triazine, quinoxaline, benzimidazole,benzotriazole, purine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole,imidazole, thiophene, furan, isobenzofuran, pyrrole, indolizine,isoindole, indole, indazole, isoquinoline, quinoline, phthalazine,naphthyridine, quinazoline, cinnoline, and pteridine.

In yet a further embodiment is a compound of Formula (III) wherein theheteroaryl is furan.

In one embodiment is a compound of Formula (III) wherein the heteroarylis thiophene.

In another embodiment is a compound of Formula (III) wherein R₁ ishydrogen.

In one aspect, described herein is a compound of Formula (V):

wherein:

-   -   Z is selected from a group consisting of aryl, heteroaryl,        arylalkyl, or heteroarylalkyl, wherein aryl, heteroaryl,        arylalkyl, or heteroarylalkyl are optionally substituted with at        least one R₁₃;    -   R₂, R₄, R₆, R₇, R₁₀, R₁₁, R₁₂, and R₁₃ are each independently        selected from a group consisting of H, F, Cl, Br, I, —CN, —NO₂,        —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₃ is selected from F, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉,        C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₁ and R₅ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₂-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a compound of Formula (VII):

wherein:

-   -   X is heterocycloalkyl, aryl, arylheteroalkyl, heteroaryl,        arylalkyl, heteroarylalkyl, 9H-xanthene; wherein        heterocycloalkyl, aryl, arylheteroalkyl, heteroaryl, arylalkyl,        heteroarylalkyl, 9H-xanthene are optionally substituted with at        least one R₂;    -   Y is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₈, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₁ and R₃ are each independently selected from hydrogen,        C₁-C₆alkyl, phenyl or benzyl;    -   R₄, R₆, R₇, and R₁₂ are each independently selected from H, F,        Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, OR₁₁, C₂-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)(R₁₀), —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₂ is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,        —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)(R₁₀),        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₅ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)(R₁₀),        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₁₀ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl or    -   R₉ and R₁₀ and the nitrogen atom to which they are attached form        a 3-8 membered heterocyclic ring;    -   each R₁₁ is independently selected from H, C₂-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In a further aspect, described herein is a compound of Formula (IX):

wherein:

-   -   R₁ and R₂ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₃ is selected from H, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₃-C₈cycloalkyl, phenyl, and benzyl;    -   R₄ and R₁₀ are each independently selected from F, Br, I, —CN,        —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₅ and R₇ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₆ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   a pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In another aspect is a compound of Formula (X):

wherein:

-   -   R₁ and R₂ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₅ and R₇ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —OCF₃, —OR₁₀, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₄, R₆, and R₁₀ are each independently selected from F, Cl, Br,        I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted aryl, optionally        substituted O-aryl, optionally substituted heteroaryl,        —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,        —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,        —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,        —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   R₁₀ is independently selected from H, C₂-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a compound of Formula (XII):

wherein:

-   -   X is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein        cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally        substituted with at least one R₄;    -   R₂ is selected from H, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl;    -   R₁ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₃ and R₇ are each independently selected from H, F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₄ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₆ and R₁₀ are each independently selected from H, F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₅ is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,        —OCF₃, —OR₉, C₁-C₃alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In another aspect is a compound of Formula (XIII):

wherein:

-   -   R₂ and R₃ are each independently H, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, and optionally substituted        heteroaryl; or    -   R₂ and R₃ together with the nitrogen atom to which they are        attached form a 3-8 membered heterocycloalkyl ring or a        6-membered heteroaryl ring;    -   R₁ is selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   R₅, R₆, R₁₀, and R₁₁ are each independently selected from H, F,        Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl,        C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,        C₂-C₈heterocycloalkyl, optionally substituted O-aryl, optionally        substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₇ is selected from H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃,        —OCF₃, —OR₉, C₂-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one aspect, described herein is a compound of Formula (XV), orpharmaceutically acceptable salt, pharmaceutically acceptable solvate,or pharmaceutically acceptable prodrug thereof:

wherein:

-   -   X is cycloalkyl, heterocycloalkyl, aryl, and heteroaryl wherein        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally        substituted with at least one R₃;    -   Y is a bond, C₁-C₆alkyl, C₂-C₆alkenyl, NR₂, O, S,        NR₂(C₁-C₆alkyl), O(C₁-C₆alkyl), S(C₁-C₆alkyl),        NR₂(C₂-C₆alkenyl), O(C₂-C₆alkenyl), S(C₂-C₆alkenyl); wherein        C₁-C₆alkyl and C₂-C₆alkenyl are optionally substituted with at        least one R₃;    -   each R₁ is independently selected from H, F, Cl, Br, I, —CN,        —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈;    -   R₂ is H, C₁-C₆alkyl, and C₃-C₈cycloalkyl;    -   R₃ and R₄ are each independently selected from F, Cl, Br, I,        —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl,        C₁-C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,        optionally substituted aryl, optionally substituted O-aryl,        optionally substituted heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂,        —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,        —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,        —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂,        —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈; or    -   two R₃ together with the atoms to which they are attached form a        heterocycloalkyl group having at least one O, NH, or S;    -   R₅ is selected from Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,        —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,        C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted        aryl, optionally substituted O-aryl, optionally substituted        heteroaryl, —NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂,        —C(═O)CF₃, —C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂,        —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉,        —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈,        and —S(═O)₂R₈;    -   each R₈ is independently selected from C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl;    -   each R₉ is independently selected from H, C₁-C₆alkyl,        C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; or a        pharmaceutically acceptable salt, pharmaceutically acceptable        solvate, or pharmaceutically acceptable prodrug thereof.

In one embodiment is a compound of Formula (XV) wherein X is aryl orheteroaryl. In another embodiment, X is aryl. In a further embodiment,aryl is phenyl. In yet another embodiment phenyl is substituted with atleast one R₃ selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃,—OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, and optionally substituted heteroaryl. In oneembodiment, R₃ is selected from F, Cl, Br, and I. In another embodiment,R₃ is OR₉. In a further embodiment, R₉ is H. In a further embodiment,the aryl group is monosubstituted, disubstituted, or trisubstituted. Inyet a further embodiment, the aryl group is disubstituted with OR₉wherein R₉ is H.

In a further embodiment two R₃ together with the atoms to which they areattached form a heterocycloalkyl group having at least one O, NH, or S.In yet a further embodiment the heterocycloalkyl group has two O atoms.In another embodiment, two R₃ together with the atoms to which they areattached form a five-membered heterocycloalkyl group having two O atoms.In yet another embodiment, two R₃ together with the atoms to which theyare attached form a six-membered heterocycloalkyl group having two Oatoms.

In one embodiment is a compound of Formula (XV) wherein X is heteroaryl.

In one embodiment is a compound of Formula (XV) wherein the heteroarylis selected from pyridine, pyrimidine, pyrazine, pyrazole, oxazole,thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, pyridazine,1,3,5-trazine, 1,2,4-triazine, quinoxaline, benzimidazole,benzotriazole, purine, 1H-[1,2,3]triazolo[4,5-d]pyrimidine, triazole,imidazole, thiophene, furan, isobenzofuran, pyrrole, indolizine,isoindole, indole, indazole, isoquinoline, quinoline, phthalazine,naphthyridine, quinazoline, cinnoline, and pteridine. In one embodiment,R₃ is selected from F, Cl, Br, and I. In another embodiment, R₃ is OR₉.In a further embodiment, R₉ is H. In a further embodiment, theheteroaryl group is monosubstituted, disubstituted, or trisubstituted.In yet a further embodiment, the heteroaryl group is disubstituted withOR₉ wherein R₉ is H.

In a further embodiment is a compound of Formula (XV) wherein Y isNR₂(C₁-C₆alkyl), O(C₁-C₆alkyl), and S(C₁-C₆alkyl). In yet a furtherembodiment Y is NR₂(C₁-C₆alkyl). In one embodiment R₂ is H. In anotherembodiment C₁-C₆alkyl is CH₂, CH₂CH₂, and CH₂CH₂CH₂. In yet anotherembodiment C₁-C₆alkyl is CH₂CH₂. In one embodiment, Y is a bond. In afurther embodiment, Y is C₁-C₆alkyl. In yet a further embodiment,C₁-C₆alkyl is CH₂, CH₂CH₂, or CH₂CH₂CH₂. In a further embodiment, Y isNR₂(C₂-C₆alkenyl), O(C₂-C₆alkenyl), or S(C₂-C₆alkenyl). In a furtherembodiment, Y is NR₂(C₂-C₆alkenyl). In yet a further embodiment,C₂-C₆alkenyl is CH₂CHCH, CH₂CH₂CHCH. In a further embodiment, R₂ is H.In another embodiment, Y is NR₂(C₁-C₆alkyl), O(C₁-C₆alkyl),S(C₁-C₆alkyl) wherein C₁-C₆alkyl is optionally substituted with at leastone group selected from F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉.In another embodiment, R₉ is H.

In yet a further embodiment is a compound of Formula (XV) wherein eachR₁ is independently H. In another embodiment, R₁ is selected from F, Cl,Br, and I.

In one aspect is a pharmaceutical composition comprising apharmaceutically acceptable diluent, excipient or binder, and a compoundof Formula (I)-(XV) and Group A or pharmaceutically acceptable salt,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof.

In another aspect is the use of a compound of Formula (I)-(XV) and GroupA or pharmaceutically acceptable salt, pharmaceutically acceptablesolvate, or pharmaceutically acceptable prodrug thereof, for theformulation of a medicament for the modulation of store operated calcium(SOC) channel activity in a subject or for the treatment of a disease orcondition in a subject that would benefit from the modulation of storeoperated calcium (SOC) channel activity.

In one embodiment is the use of a compound of Formula (I)-(XV) and GroupA which inhibits store operated calcium entry (SOCE). In anotherembodiment, is the use of a compound of Formula (I)-(XV) and Group A,wherein the store operated calcium channel activity is calcium releaseactivated calcium channel activity.

In one aspect is an article of manufacture, comprising packagingmaterial, a compound of Formula (I)-(XV) and Group A, or composition, orpharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, which is effective forinhibiting calcium release-activated calcium (CRAC) channel activity, orfor the treatment, prevention or amelioration of one or more symptoms ofa disease or condition that would benefit from the inhibition of calciumrelease-activated calcium (CRAC) channel activity, within the packagingmaterial, and a label that indicates that the compound or composition,or pharmaceutically acceptable salt, pharmaceutically acceptableprodrug, or pharmaceutically acceptable solvate thereof, is used for theinhibition of calcium release-activated calcium (CRAC) channel activity,or for the treatment, prevention or amelioration of one or more symptomsof a disease or condition that would benefit from the inhibition ofcalcium release-activated calcium (CRAC) channel activity. In anotherembodiment, is an article of manufacture wherein the compound of Formula(I)-(XV) and Group A inhibits store operated calcium entry (SOCE).

Further Forms of Compounds

In some embodiments, the compounds described herein exist asdiastereomers, enantiomers, or other stereoisomerism forms. Thecompounds presented herein include all diastereomeric, enantiomeric, andepimeric forms as well as the appropriate mixtures thereof. Separationof stereoisomers are performed by chromatography or by the formingdiastereomeric and separation by recrystallization, or chromatography,or any combination thereof. (Jean Jacques, Andre Collet, Samuel H.Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons,Inc., 1981, the separation of stereoisomers as discussed in thisreference is herein incorporated). In other embodiments, stereoisomersare obtained by stereoselective synthesis.

In some situations, compounds exist as tautomers. All tautomers areincluded within the formulas described herein.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).The compounds described herein are in the form of pharmaceuticallyacceptable salts. As well, active metabolites of these compounds havingthe same type of activity are included in the scope of the presentdisclosure. In addition, in other embodiments, the compounds describedherein exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug. In someother embodiments, the prodrug is bioavailable by oral administrationwhereas the parent is not. In other embodiments, the prodrug also hasimproved solubility in pharmaceutical compositions over the parent drug.An example, without limitation, of a prodrug would be a compounddescribed herein, which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. In other embodiments, the prodrug is ashort peptide (polyaminoacid) bonded to an acid group where the peptideis metabolized to reveal the active moiety. In certain embodiments, uponin vivo administration, a prodrug is chemically converted to thebiologically, pharmaceutically or therapeutically active form of thecompound. In certain embodiments, a prodrug is enzymatically metabolizedby one or more steps or processes to the biologically, pharmaceuticallyor therapeutically active form of the compound.

To produce a prodrug, a pharmaceutically active compound is modifiedsuch that the active compound will be regenerated upon in vivoadministration. In other embodiments, the prodrug is designed to alterthe metabolic stability or the transport characteristics of a drug, tomask side effects or toxicity, to improve the flavor of a drug or toalter other characteristics or properties of a drug.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I)-(XV) and GroupA as set forth herein are included within the scope of the claims. Insome cases, some of the herein-described compounds are a prodrug foranother derivative or active compound.

In some embodiments are prodrugs that are designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility.

In some embodiments, sites on the aromatic ring portion of compoundsdescribed herein are susceptible to various metabolic reactions,therefore incorporation of appropriate substituents on the aromatic ringstructures, such as, by way of example only, halogens can reduce,minimize or eliminate this metabolic pathway.

In other embodiments, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by other means, including,but not limited to, the use of chromophores or fluorescent moieties,bioluminescent labels, photoactivatable or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. In other embodimentsare examples of isotopes that are incorporated into the presentcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,fluorine and chlorine, such as, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively. Certain isotopically-labeledcompounds described herein, for example those into which radioactiveisotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/orsubstrate tissue distribution assays. Further, in some otherembodiments, substitution with isotopes such as deuterium, i.e., ²H,affords certain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements.

In further embodiments, the compounds described herein are metabolizedupon administration to an organism in need to produce a metabolite thatis then used to produce a desired effect, including a desiredtherapeutic effect.

Compounds described herein are formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid, such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, metaphosphoric acid,and the like; or with an organic acid, such as, for example, aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaricacid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, toluenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, butyric acid, phenylacetic acid,phenylbutyric acid, valproic acid, and the like; (2) salts formed whenan acidic proton present in the parent compound is replaced by a metalion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium), analkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion. Insome cases, compounds described herein coordinate with an organic base,such as, but not limited to, ethanolamine, diethanolamine,triethanolamine, tromethamine, N-methylglucamine, dicyclohexylamine,tris(hydroxymethyl)methylamine. In other cases, compounds describedherein form salts with amino acids such as, but not limited to,arginine, lysine, and the like. Acceptable inorganic bases used to formsalts with compounds that include an acidic proton, include, but are notlimited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and in someembodiments are formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. In some embodiments, solvates ofcompounds described herein are conveniently prepared or formed duringthe processes described herein. In other embodiments the compoundsprovided herein exist in unsolvated as well as solvated forms. Ingeneral, the solvated forms are considered equivalent to the unsolvatedforms for the purposes of the compounds and methods provided herein.

In other embodiments, compounds described herein, such as compounds ofFormula (I)-(XV) and Group A, are in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, melting points,density, hardness, crystal shape, optical properties, stability, andsolubility. Various factors such as the recrystallization solvent, rateof crystallization, and storage temperature may cause a single crystalform to dominate.

In further embodiments, the screening and characterization of thepharmaceutically acceptable salts, polymorphs and/or solvates areaccomplished using a variety of techniques including, but not limitedto, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption,and microscopy. Thermal analysis methods address thermo chemicaldegradation or thermo physical processes including, but not limited to,polymorphic transitions, and such methods are used to analyze therelationships between polymorphic forms, determine weight loss, to findthe glass transition temperature, or for excipient compatibilitystudies. Such methods include, but are not limited to, Differentialscanning calorimetry (DSC), Modulated Differential Scanning Calorimetry(MDCS), Thermogravimetric analysis (TGA), and Thermogravi-metric andInfrared analysis (TG/IR). X-ray diffraction methods include, but arenot limited to, single crystal and powder diffractometers andsynchrotron sources. The various spectroscopic techniques used include,but are not limited to, Raman, FTIR, UV-VIS, and NMR (liquid and solidstate). The various microscopy techniques include, but are not limitedto, polarized light microscopy, Scanning Electron Microscopy (SEM) withEnergy Dispersive X-Ray Analysis (EDX), Environmental Scanning ElectronMicroscopy with EDX (in gas or water vapor atmosphere), IR microscopy,and Raman microscopy.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof.

The starting materials and reagents used for the synthesis of thecompounds described herein are synthesized or are obtained fromcommercial sources, such as, but not limited to, Sigma-Aldrich,FischerScientific (Fischer Chemicals), and AcrosOrganics.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein as well as other techniques, such as described, forexample, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds,Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989);Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989),March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey andSundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS3^(rd) Ed., (Wiley 1999) (the synthetic techniques described in theabove publications are herein incorporated by reference). Generalmethods for the preparation of compound as disclosed herein are derivedfrom known reactions, and in some embodiments, the reactions aremodified by the use of appropriate reagents and conditions, for theintroduction of the various moieties found in the formulae as providedherein. As a guide the following synthetic methods are utilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

In some embodiments, the compounds described herein are modified usingvarious electrophiles and/or nucleophiles to form new functional groupsor substituents. Table 2 entitled “Examples of Covalent Linkages andPrecursors Thereof” lists selected non-limiting examples of covalentlinkages and precursor functional groups which yield the covalentlinkages. Table 2 is used as guidance toward the variety ofelectrophiles and nucleophiles combinations available that providecovalent linkages. Precursor functional groups are shown aselectrophilic groups and nucleophilic groups.

TABLE 2 Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Alkyl amines alkylhalides amines/anilines Esters alkyl halides carboxylic acids Thioethersalkyl halides Thiols Ethers alkyl halides alcohols/phenols Thioethersalkyl sulfonates Thiols Esters Anhydrides alcohols/phenols CarboxamidesAnhydrides amines/anilines Thiophenols aryl halides Thiols Aryl aminesaryl halides Amines Thioethers Azindines Thiols Carboxamides carboxylicacids amines/anilines Esters carboxylic acids Alcohols hydrazinesHydrazides carboxylic acids N-acylureas or Anhydrides carbodiimidescarboxylic acids Esters diazoalkanes carboxylic acids ThioethersEpoxides Thiols Thioethers haloacetamides Thiols Ureas Isocyanatesamines/anilines Urethanes Isocyanates alcohols/phenols Thioureasisothiocyanates amines/anilines Thioethers Maleimides Thiols Alkylamines sulfonate esters amines/anilines Thioethers sulfonate estersThiols Sulfonamides sulfonyl halides amines/anilines Sulfonate esterssulfonyl halides phenols/alcoholsUse of Protecting Groups

In some embodiments, in the reactions described, it is necessary toprotect reactive functional groups, for example hydroxy, amino, imino,thio or carboxy groups, where these are desired in the final product, inorder to avoid their unwanted participation in reactions. Protectinggroups are used to block some or all of the reactive moieties andprevent such groups from participating in chemical reactions until theprotective group is removed. In some embodiments, each protective groupis removable by a different means. Protective groups that are cleavedunder totally disparate reaction conditions fulfill the requirement ofdifferential removal.

In other embodiments, protective groups are removed by acid, base,reducing conditions (such as, for example, hydrogenolysis), and/oroxidative conditions. In other embodiments, groups such as trityl,dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and areused to protect carboxy and hydroxy reactive moieties in the presence ofamino groups protected with Cbz groups, which are removable byhydrogenolysis, and Fmoc groups, which are base labile. In furtherembodiments, carboxylic acid and hydroxy reactive moieties are blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

In yet further embodiments, carboxylic acid and hydroxy reactivemoieties are blocked with hydrolytically removable protective groupssuch as the benzyl group, while amine groups capable of hydrogen bondingwith acids are blocked with base labile groups such as Fmoc. In otherembodiments, carboxylic acid reactive moieties are protected byconversion to simple ester compounds as exemplified herein, whichinclude conversion to alkyl esters, or they are blocked withoxidatively-removable protective groups such as 2,4-dimethoxybenzyl,while co-existing amino groups are blocked with fluoride labile silylcarbamates.

In further embodiments, allyl blocking groups are useful in thenpresence of acid- and base-protecting groups since the former are stableand are subsequently removed by metal or pi-acid catalysts. For example,an allyl-blocked carboxylic acid is deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate is attached. As long as theresidue is attached to the resin, that functional group is blocked andcannot react. Once released from the resin, the functional group isavailable to react.

Typically, in some embodiments, blocking/protecting groups are selectedfrom:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, the discussionof protecting groups in the above publication is herein incorporated byreference for such disclosure.

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood in the field to whichthe claimed subject matter belongs. In the event that there is aplurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation is found by searching the internet. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

Definition of standard chemistry terms are found in reference works,including but not limited to, Carey and Sundberg “ADVANCED ORGANICCHEMISTRY 4^(TH) ED.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology, within the skill of the art areemployed.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those known in the art. Insome embodiments, standard techniques are used for chemical syntheses,chemical analyses, pharmaceutical preparation, formulation, anddelivery, and treatment of patients. In other embodiments, standardtechniques are used for recombinant DNA, oligonucleotide synthesis, andtissue culture and transformation (e.g., electroporation, lipofection).In further embodiments, reactions and purification techniques areperformed e.g., using kits of manufacturer's specifications or ascommonly accomplished in the art or as described herein. The foregoingtechniques and procedures are generally performed of conventionalmethods and as described in various general and more specific referencesthat are cited and discussed throughout the present specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. In someembodiments, the alkyl groups include or do not include units ofunsaturation. In some embodiments, the alkyl moiety is a “saturatedalkyl” group, which means that it does not contain any units ofunsaturation (i.e. a carbon-carbon double bond or a carbon-carbon triplebond). In further embodiments, the alkyl group also is an “unsaturatedalkyl” moiety, which means that it contains at least one unit ofunsaturation. In some embodiments, the alkyl moiety, whether saturatedor unsaturated, is branched, straight chain, or cyclic.

In other embodiments, the “alkyl” group has 1 to 6 carbon atoms(whenever it appears herein, a numerical range such as “1 to 6” refersto each integer in the given range; e.g., “1 to 6 carbon atoms” meansthat the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 6 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated). The alkyl group of the compoundsdescribed herein are designated as “C₁-C₆ alkyl” or similardesignations. By way of example only, “C₁-C₆ alkyl” indicates that thereare one to six carbon atoms in the alkyl chain, i.e., the alkyl chain isselected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl,iso-pentyl, neo-pentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl. In someembodiments, alkyl groups are substituted or unsubstituted. In otherembodiments, depending on the structure, an alkyl group is a monoradicalor a diradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a double bond that is not part of anaromatic group. That is, an alkenyl group begins with the atoms—C(R)═CR₂, wherein R refers to the remaining portions of the alkenylgroup, which are the same or different. Non-limiting examples of analkenyl group include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and—C(CH₃)═CHCH₃. The alkenyl moiety are branched, straight chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups aresubstituted or unsubstituted. In some other embodiments, depending onthe structure, an alkenyl group is a monoradical or a diradical (i.e.,an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the firsttwo atoms of the alkyl group form a triple bond. That is, an alkynylgroup begins with the atoms —C≡C—R, wherein R refers to the remainingportions of the alkynyl group. Non-limiting examples of an alkynyl groupinclude —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. In otherembodiments, the “R” portion of the alkynyl moiety is branched, straightchain, or cyclic. An alkynyl group can have 2 to 6 carbons. Alkynylgroups are substituted or unsubstituted. In some embodiments, dependingon the structure, an alkynyl group is a monoradical or a diradical(i.e., an alkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. In some embodiments, when x=2, thealkyl groups, taken together with the nitrogen to which they areattached, optionally form a cyclic ring system. “Dialkylamino” refers toa —N(alkyl)₂ group, where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2 π electrons, where n is an integer. Inother embodiments, aromatic rings are formed from five, six, seven,eight, nine, or more than nine atoms. In some other embodiments,aromatics are optionally substituted. The term “aromatic” includes botharyl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g.,pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In further embodiments,aryl rings are formed by five, six, seven, eight, nine, or more thannine carbon atoms. In some embodiments, aryl groups are optionallysubstituted. Examples of aryl groups include, but are not limited tophenyl, and naphthalenyl. In other embodiments, depending on thestructure, an aryl group is a monoradical or a diradical (i.e., anarylene group).

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to benzyl, 2-phenylethyl, -phenylpropyl,1-methyl-3-phenylpropyl, and 2-naphth-2-ylethyl.

“Carboxy” refers to —CO₂H. In some cases, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. In some embodiments, cycloalkyls are saturated,or partially unsaturated. In other embodiments, cycloalkyls are fusedwith an aromatic ring (in which case the cycloalkyl is bonded through anon-aromatic ring carbon atom). Cycloalkyl groups include groups havingfrom 3 to 10 ring atoms. Illustrative examples of cycloalkyl groupsinclude, but are not limited to, the following moieties:

and the like.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. In some embodiments,polycyclic heteroaryl groups are fused or non-fused. Illustrativeexamples of heteroaryl groups include the following moieties:

and the like.

The term “heteroarylalkyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heteroarylalkylinclude, but are not limited to, pyridinylmethyl.

The term “heteroarylalkenyl” as used herein, means a heterocycle, asdefined herein, appended to the parent molecular moiety through analkenyl group, as defined herein.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. In someembodiments, the radicals are fused with an aryl or heteroaryl.Illustrative examples of heterocycloalkyl groups, also referred to asnon-aromatic heterocycles, include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring).

The term “heterocycloalkylalkyl” as used herein, means a heterocycle, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens. In some embodiments, the halogens are the same orthey are different. Non-limiting examples of haloalkyls include —CH₂Cl,—CF₃, —CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.In some embodiments, the heteroatom(s) are placed at any interiorposition of the heteroalkyl group. Examples include, but are not limitedto, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In some embodiments, up to twoheteroatoms are consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a“heteroalkyl” may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, halo,acyl, acyloxy, —CO₂H, —CO₂—alkyl, nitro, haloalkyl, fluoroalkyl, andamino, including mono- and di-substituted amino groups (e.g. —NH₂, —NHR,—N(R)₂), and the protected derivatives thereof. By way of example, anoptional substituents is L^(s)R^(s), wherein each L^(s) is independentlyselected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)₂—, —NH—,—NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂, —OC(O)NH—, —NHC(O)O—,—(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and each R^(s) is independentlyselected from among H, (C₁-C₆alkyl), (C₃-C₈cycloalkyl), aryl,heteroaryl, heterocycloalkyl, and C₁-C₆heteroalkyl. In some embodiments,the protecting groups that form the protective derivatives of the abovesubstituents are found in sources such as Greene and Wuts, above.

The methods and formulations described herein include the use ofcrystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds having the structure of Formula (I), aswell as active metabolites of these compounds having the same type ofactivity. In some situations, compounds exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In some embodiments, the compounds described herein exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease, disorder or conditionsymptoms, preventing additional symptoms, ameliorating or preventing theunderlying causes of symptoms, inhibiting the disease, disorder orcondition, e.g., arresting the development of the disease, disorder orcondition, relieving the disease, disorder or condition, causingregression of the disease, disorder or condition, relieving a conditioncaused by the disease, disorder or condition, or stopping the symptomsof the disease, disorder or condition either prophylactically and/ortherapeutically.

As used herein, the term “target protein” refers to a protein or aportion of a protein capable of being bound by, or interacting with acompound described herein, such as a compound of Formula (I)-(XV) andGroup A. In certain embodiments, a target protein is a STIM protein. Incertain embodiments, a target protein is an Orai protein.

As used herein, “STIM protein” includes but is not limited to, mammalianSTIM-1, such as human and rodent (e.g., mouse) STIM-1, Drosophilamelanogaster D-STIM, C. elegans C-STIM, Anopheles gambiae STIM andmammalian STIM-2, such as human and rodent (e.g., mouse) STIM-2. Asdescribed herein, such proteins have been identified as being involvedin, participating in and/or providing for store-operated calcium entryor modulation thereof, cytoplasmic calcium buffering and/or modulationof calcium levels in or movement of calcium into, within or out ofintracellular calcium stores (e.g., endoplasmic reticulum).

As used herein, an “Orai protein” includes Orai1 (SEQ ID NO: 1 asdescribed in WO 07/081,804), Orai2 (SEQ ID NO: 2 as described in WO07/081,804), or Orai3 (SEQ ID NO: 3 as described in WO 07/081,804).Orai1 nucleic acid sequence corresponds to GenBank accession numberNM_(—)032790, Orai2 nucleic acid sequence corresponds to GenBankaccession number BC069270 and Orai3 nucleic acid sequence corresponds toGenBank accession number NM_(—)152288. As used herein, Orai refers toany one of the Orai genes, e.g., Orai1, Orai2, Orai3 (see Table I of WO07/081,804). As described herein, such proteins have been identified asbeing involved in, participating in and/or providing for store-operatedcalcium entry or modulation thereof, cytoplasmic calcium bufferingand/or modulation of calcium levels in or movement of calcium into,within or out of intracellular calcium stores (e.g., endoplasmicreticulum).

The term “fragment” or “derivative” when referring to a protein (e.g.STIM, Orai) means proteins or polypeptides which retain essentially thesame biological function or activity in at least one assay as the nativeprotein(s). For example, the fragments or derivatives of the referencedprotein maintains at least about 50% of the activity of the nativeproteins, at least about 75%, at least about 95% of the activity of thenative proteins, as determined e.g. by a calcium influx assay.

As used herein, amelioration of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that are attributed to orassociated with administration of the compound or composition.

The term “modulate,” as used herein, means to interact with a targetprotein either directly or indirectly so as to alter the activity of thetarget protein, including, by way of example only, to inhibit theactivity of the target, or to limit or reduce the activity of thetarget.

As used herein, the term “modulator” refers to a compound that alters anactivity of a target. For example, in some embodiments, a modulatorcauses an increase or decrease in the magnitude of a certain activity ofa target compared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a target. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a target.

As used herein, “modulation” with reference to intracellular calciumrefers to any alteration or adjustment in intracellular calciumincluding but not limited to alteration of calcium concentration in thecytoplasm and/or intracellular calcium storage organelles, e.g.,endoplasmic reticulum, and alteration of the kinetics of calcium fluxesinto, out of and within cells. In aspect, modulation refers toreduction.

The terms “inhibits”, “inhibiting”, or “inhibitor” of SOC channelactivity or CRAC channel activity, as used herein, refer to inhibitionof store operated calcium channel activity or calcium release activatedcalcium channel activity.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material is administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that one activeingredient, e.g. a compound of Formula (I)-(XV) and Group A, and aco-agent, are both administered to a patient simultaneously in the formof a single entity or dosage. The term “non-fixed combination” meansthat one active ingredient, e.g. a compound of Formula (I)-(XV) andGroup A, and a co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially with nospecific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. Thelatter also applies to cocktail therapy, e.g. the administration ofthree or more active ingredients.

The term “pharmaceutical composition” refers to a mixture of a compoundof Formula (I)-(XV) and Group A described herein with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Multiple techniques of administering a compound exist inthe art including, but not limited to: intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result isreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition that includes a compound of Formula (I)-(XV) and Group Adescribed herein required to provide a clinically significant decreasein disease symptoms. In some embodiments, an appropriate “effective”amount in any individual case is determined using techniques, such as adose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. In some embodiments,diluents are used to stabilize compounds because they provide a morestable environment. Salts dissolved in buffered solutions (which alsoprovide pH control or maintenance) are utilized as diluents, including,but not limited to a phosphate buffered saline solution.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, in some embodiments, enzymes produce specific structuralalterations to a compound. For example, cytochrome P450 catalyzes avariety of oxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulphydryl groups. Further informationon metabolism are obtained from The Pharmacological Basis ofTherapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein are identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds.

“Bioavailability” refers to the percentage of the weight of the compounddisclosed herein (e.g. compound of Formula (I)-(XV) and Group A), thatis delivered into the general circulation of the animal or human beingstudied. The total exposure (AUC(0-∞)) of a drug when administeredintravenously is usually defined as 100% bioavailable (F %). “Oralbioavailability” refers to the extent to which a compound disclosedherein, is absorbed into the general circulation when the pharmaceuticalcomposition is taken orally as compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of a compoundof Formula (I)-(XV) and Group A disclosed herein, in the plasmacomponent of blood of a subject. It is understood that the plasmaconcentration of compounds described herein may vary significantlybetween subjects, due to variability with respect to metabolism and/orpossible interactions with other therapeutic agents. In accordance withone embodiment disclosed herein, the blood plasma concentration of thecompounds disclosed herein varies from subject to subject. Likewise, insome embodiments, values such as maximum plasma concentration (C_(max))or time to reach maximum plasma concentration (T_(max)), or total areaunder the plasma concentration time curve (AUC(0-∞)) varies from subjectto subject. Due to this variability, the amount necessary to constitute“a therapeutically effective amount” of a compound will vary fromsubject to subject.

As used herein, “calcium homeostasis” refers to the maintenance of anoverall balance in intracellular calcium levels and movements, includingcalcium signaling, within a cell.

As used herein, “intracellular calcium” refers to calcium located in acell without specification of a particular cellular location. Incontrast, “cytosolic” or “cytoplasmic” with reference to calcium refersto calcium located in the cell cytoplasm.

As used herein, an effect on intracellular calcium is any alteration ofany aspect of intracellular calcium, including but not limited to, analteration in intracellular calcium levels and location and movement ofcalcium into, out of or within a cell or intracellular calcium store ororganelle. For example, in some embodiments, an effect on intracellularcalcium is an alteration of the properties, such as, for example, thekinetics, sensitivities, rate, amplitude, and electrophysiologicalcharacteristics, of calcium flux or movement that occurs in a cell orportion thereof. In some embodiments, an effect on intracellular calciumis an alteration in any intracellular calcium-modulating process,including, store-operated calcium entry, cytosolic calcium buffering,and calcium levels in or movement of calcium into, out of or within anintracellular calcium store. Any of these aspects are assessed in avariety of ways including, but not limited to, evaluation of calcium orother ion (particularly cation) levels, movement of calcium or other ion(particularly cation), fluctuations in calcium or other ion(particularly cation) levels, kinetics of calcium or other ion(particularly cation) fluxes and/or transport of calcium or other ion(particularly cation) through a membrane. An alteration is any suchchange that is statistically significant. Thus, for example, in someembodiments, if intracellular calcium in a test cell and a control cellis said to differ, such differences are a statistically significantdifference.

As used herein, “involved in” with respect to the relationship between aprotein and an aspect of intracellular calcium or intracellular calciumregulation means that when expression or activity of the protein in acell is reduced, altered or eliminated, there is a concomitant orassociated reduction, alteration or elimination of one or more aspectsof intracellular calcium or intracellular calcium regulation. Such analteration or reduction in expression or activity can occur by virtue ofan alteration of expression of a gene encoding the protein or byaltering the levels of the protein. A protein involved in an aspect ofintracellular calcium, such as, for example, store-operated calciumentry, thus, are one that provides for or participates in an aspect ofintracellular calcium or intracellular calcium regulation. For example,a protein that provides for store-operated calcium entry are a STIMprotein and/or an Orai protein.

As used herein, a protein that is a component of a calcium channel is aprotein that participates in multi-protein complex that forms thechannel.

As used herein, “cation entry” or “calcium entry” into a cell refers toentry of cations, such as calcium, into an intracellular location, suchas the cytoplasm of a cell or into the lumen of an intracellularorganelle or storage site. Thus, in some embodiments, cation entry is,for example, the movement of cations into the cell cytoplasm from theextracellular medium or from an intracellular organelle or storage site,or the movement of cations into an intracellular organelle or storagesite from the cytoplasm or extracellular medium. Movement of calciuminto the cytoplasm from an intracellular organelle or storage site isalso referred to as “calcium release” from the organelle or storagesite.

As used herein, “protein that modulates intracellular calcium” refers toany cellular protein that is involved in regulating, controlling and/oraltering intracellular calcium. For example, in some embodiments, such aprotein is involved in altering or adjusting intracellular calcium in anumber of ways, including, but not limited to, through the maintenanceof resting or basal cytoplasmic calcium levels, or through involvementin a cellular response to a signal that is transmitted in a cell througha mechanism that includes a deviation in intracellular calcium fromresting or basal states. In the context of a “protein that modulatesintracellular calcium,” a “cellular” protein is one that is associatedwith a cell, such as, for example, a cytoplasmic protein, a plasmamembrane-associated protein or an intracellular membrane protein.Proteins that modulate intracellular calcium include, but are notlimited to, ion transport proteins, calcium-binding proteins andregulatory proteins that regulate ion transport proteins.

As used herein, “amelioration” refers to an improvement in a disease orcondition or at least a partial relief of symptoms associated with adisease or condition.

As used herein, “cell response” refers to any cellular response thatresults from ion movement into or out of a cell or within a cell. Insome embodiments, the cell response is associated with any cellularactivity that is dependent, at least in part, on ions such as, forexample, calcium. Such activities may include, for example, cellularactivation, gene expression, endocytosis, exocytosis, cellulartrafficking and apoptotic cell death.

As used herein, “immune cells” include cells of the immune system andcells that perform a function or activity in an immune response, suchas, but not limited to, T-cells, B-cells, lymphocytes, macrophages,dendritic cells, neutrophils, eosinophils, basophils, mast cells, plasmacells, white blood cells, antigen presenting cells and natural killercells.

As used herein, “cytokine” refers to small soluble proteins secreted bycells that in some embodiments, alter the behavior or properties of thesecreting cell or another cell. Cytokines bind to cytokine receptors andtrigger a behavior or property within the cell, for example, cellproliferation, death or differentiation. Exemplary cytokines include,but are not limited to, interleukins (e.g., IL-2, IL-3, IL-4, IL-5,IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-15, IL-16, IL-17,IL-18, IL-1α, IL-1β, and IL-1 RA), granulocyte colony stimulating factor(G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF),oncostatin M, erythropoietin, leukemia inhibitory factor (LIF),interferons, B7.1 (also known as CD80), B7.2 (also known as B70, CD86),TNF family members (TNF-α, TNF-β, LT-β, CD40 ligand, Fas ligand, CD27ligand, CD30 ligand, 4-1BBL, Trail), and MIF.

“Store operated calcium entry” or “SOCE” refers to the mechanism bywhich release of calcium ions from intracellular stores is coordinatedwith ion influx across the plasma membrane.

“Selective inhibitor of SOC channel activity” means that the inhibitoris selective for SOC channels and does not substantially affect theactivity of other types of ion channels.

“Selective inhibitor of CRAC channel activity” means that the inhibitoris selective for CRAC channels and does not substantially affect theactivity of other types of ion channels and/or other SOC channels.

Examples of Pharmaceutical Compositions and Methods of Administration

Pharmaceutical compositions are formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which are used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Insome embodiments, any of the well-known techniques, carriers, andexcipients are used as suitable. In some embodiments, a summary ofpharmaceutical compositions described herein are found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),the pharmaceutical compositions described in the above publications areherein incorporated by reference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I)-(XV) and Group A described herein, with otherchemical components, such as carriers, stabilizers, diluents, dispersingagents, suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. In practicing the methods of treatment or use providedherein, therapeutically effective amounts of compounds described hereinare administered in a pharmaceutical composition to a mammal having adisease, disorder, or condition to be treated. In some embodiments, themammal is a human. In some embodiments, a therapeutically effectiveamount varies widely depending on the severity of the disease, the ageand relative health of the subject, the potency of the compound used andother factors. In some embodiments, the compounds of Formula (I)-(XV)and Group A are used singly or in combination with one or moretherapeutic agents as components of mixtures (as in combinationtherapy).

In further embodiments, the pharmaceutical formulations described hereinare administered to a subject by multiple administration routes,including but not limited to, oral, parenteral (e.g., intravenous,subcutaneous, intramuscular), intranasal, buccal, topical, rectal, ortransdermal administration routes. Moreover, in some embodiments, thepharmaceutical compositions described herein, which include a compoundof Formula (I)-(XV) and Group A described herein, are formulated intoany suitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions,aerosols, controlled release formulations, fast melt formulations,effervescent formulations, lyophilized formulations, tablets, powders,pills, dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations.

In some embodiments, the compounds and/or compositions are administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ or tissue, often in a depotpreparation or sustained release formulation. In other embodiments, suchlong acting formulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in some embodiments, the drug is administered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. The liposomes will be targeted to and taken upselectively by the organ. In some embodiments, the drug is provided inthe form of a rapid release formulation, in the form of an extendedrelease formulation, or in the form of an intermediate releaseformulation.

In some embodiments, pharmaceutical compositions including a compounddescribed herein is manufactured in a conventional manner, such as, byway of example only, by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or compression processes.

The pharmaceutical compositions will include at least one compound ofFormula (I)-(XV) and Group A described herein, as an active ingredientin free-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical compositions describedherein include the use of crystalline forms (also known as polymorphs),as well as active metabolites of these compounds having the same type ofactivity.

In certain embodiments, compositions provided herein also include one ormore preservatives to inhibit microbial activity. Suitable preservativesinclude quaternary ammonium compounds such as benzalkonium chloride,cetyltrimethylammonium bromide and cetylpyridinium chloride.

In some embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein (e.g. compounds of Formula (I)-(XV) and GroupA), optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets, pills, or capsules. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inother embodiments, disintegrating agents are added, such as thecross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, oralginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose, insome embodiments, concentrated sugar solutions are used, whichoptionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. In some embodiments,dyestuffs or pigments are added to the tablets or dragee coatings foridentification or to characterize different combinations of activecompound doses.

In further embodiments, pharmaceutical preparations that are used orallyinclude push-fit capsules made of gelatin, as well as soft, sealedcapsules made of gelatin and a plasticizer, such as glycerol orsorbitol. In some embodiments, the push-fit capsules contain the activeingredients in admixture with filler such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In some embodiments, are soft capsules, whereinthe active compounds are dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Insome embodiments stabilizers are added.

In some embodiments, the solid dosage forms disclosed herein are in theform of a tablet, (including a suspension tablet, a fast-melt tablet, abite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder), acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations of the compounds described herein areadministered as a single capsule or in multiple capsule dosage form. Insome embodiments, the pharmaceutical formulation is administered in two,or three, or four, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula (I)-(XV) and Group A described herein, with one or morepharmaceutical excipients to form a bulk blend composition. Whenreferring to these bulk blend compositions as homogeneous, it is meantthat the particles of the compound of Formula (I) described herein, aredispersed evenly throughout the composition so that the composition arereadily subdivided into equally effective unit dosage forms, such astablets, pills, and capsules. In some embodiments, the individual unitdosages also include film coatings, which disintegrate upon oralingestion or upon contact with diluent. In further embodiments, theseformulations are manufactured by conventional pharmacologicaltechniques.

In some embodiments, the pharmaceutical solid dosage forms describedherein include a compound of Formula (I)-(XV) and Group A describedherein, and one or more pharmaceutically acceptable additives such as acompatible carrier, binder, filling agent, suspending agent, flavoringagent, sweetening agent, disintegrating agent, dispersing agent,surfactant, lubricant, colorant, diluent, solubilizer, moistening agent,plasticizer, stabilizer, penetration enhancer, wetting agent,anti-foaming agent, antioxidant, preservative, or one or morecombination thereof. In still other embodiments, using standard coatingprocedures, such as those described in Remington's PharmaceuticalSciences, 20th Edition (2000), a film coating is provided around theformulation of the compound described herein. In one embodiment, some orall of the particles of the compound described herein are coated. Inanother embodiment, some or all of the particles of the compounddescribed herein are microencapsulated. In still another embodiment, theparticles of the compound described herein are not microencapsulated andare uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of Formula (I)-(XV) and Group A from asolid dosage form matrix as efficiently as possible, disintegrants areoften used in the formulation, especially when the dosage forms arecompressed with binder. Disintegrants help rupturing the dosage formmatrix by swelling or capillary action when moisture is absorbed intothe dosage form. Suitable disintegrants for use in the solid dosageforms described herein include, but are not limited to, natural starchsuch as corn starch or potato starch, a pregelatinized starch such asNational 1551 or Amijel®, or sodium starch glycolate such as Promogel®or Explotab®, a cellulose such as a wood product, methylcrystallinecellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105,Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®,methylcellulose, croscarmellose, or a cross-linked cellulose, such ascross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that insome embodiments, are filled into soft or hard shell capsules and fortablet formulation, they ensure the tablet remaining intact aftercompression and help assure blend uniformity prior to a compression orfill step. Materials suitable for use as binders in the solid dosageforms described herein include, but are not limited to,carboxymethylcellulose, methylcellulose (e.g., Methocel®),hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603,hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS),hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®), microcrystalline dextrose, amylose, magnesium aluminumsilicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of about 20 to about 70% are used inpowder-filled gelatin capsule formulations. In some embodiments, binderusage level in tablet formulations varies whether direct compression,wet granulation, roller compaction, or usage of other excipients such asfillers which itself act as moderate binder. In some embodiments, aretablet formulations comprising binder usage levels of up to about 70%.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., in someembodiments, the polyethylene glycol has a molecular weight of about 300to about 6000, or about 3350 to about 4000, or about 5400 to about 7000,vinyl pyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

It should be appreciated that there is considerable overlap betweenadditives used in the solid dosage forms described herein. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that are included in solid dosageforms of the pharmaceutical compositions described herein.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. In some embodiments, suitableplasticizers are added from about 0.01% to about 50% by weight (w/w) ofthe coating composition. Plasticizers include, but are not limited to,diethyl phthalate, citrate esters, polyethylene glycol, glycerol,acetylated glycerides, triacetin, polypropylene glycol, polyethyleneglycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol,stearate, and castor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating provides a delayed releaseof the compounds of Formula (I) described herein from the formulation.In other embodiments, the film coating aids in patient compliance (e.g.,Opadry® coatings or sugar coating). Film coatings including Opadry®typically range from about 1% to about 3% of the tablet weight. In otherembodiments, the compressed tablets include one or more excipients.

In some embodiments, a capsule is prepared, for example, by placing thebulk blend of the formulation of the compound described above, inside ofa capsule. In some embodiments, the formulations (non-aqueoussuspensions and solutions) are placed in a soft gelatin capsule. Inother embodiments, the formulations are placed in standard gelatincapsules or non-gelatin capsules such as capsules comprising HPMC. Inother embodiments, the formulation is placed in a sprinkle capsule,wherein the capsule is swallowed whole or the capsule is opened and thecontents sprinkled on food prior to eating. In some embodiments, thetherapeutic dose is split into multiple (e.g., two, three, or four)capsules. In some embodiments, the entire dose of the formulation isdelivered in a capsule form.

In various embodiments, the particles of the compound of Formula(I)-(XV) and Group A described herein and one or more excipients are dryblended and compressed into a mass, such as a tablet, having a hardnesssufficient to provide a pharmaceutical composition that substantiallydisintegrates within less than about 30 minutes, less than about 35minutes, less than about 40 minutes, less than about 45 minutes, lessthan about 50 minutes, less than about 55 minutes, or less than about 60minutes, after oral administration, thereby releasing the formulationinto the gastrointestinal fluid.

In another formulation, dosage forms include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds described herein, which sufficientlyisolate the compound from other non-compatible excipients. Materialscompatible with compounds of Formula (I) described herein are those thatdelay the release of the compounds of Formula (I) in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds of Formula (I) described herein areformulated by methods which in some embodiments, include, e.g., spraydrying processes, spinning disk-solvent processes, hot melt processes,spray chilling methods, fluidized bed, electrostatic deposition,centrifugal extrusion, rotational suspension separation, polymerizationat liquid-gas or solid-gas interface, pressure extrusion, or sprayingsolvent extraction bath. In addition to these, in some otherembodiments, several chemical techniques, e.g., complex coacervation,solvent evaporation, polymer-polymer incompatibility, interfacialpolymerization in liquid media, in situ polymerization, in-liquiddrying, and desolvation in liquid media are used. Furthermore, in otherembodiments, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating also areused.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When such salts are added to water, the acidsand the base react to liberate carbon dioxide gas, thereby causing“effervescence.” Examples of effervescent salts include, e.g., thefollowing ingredients: sodium bicarbonate or a mixture of sodiumbicarbonate and sodium carbonate, citric acid and/or tartaric acid. Anyacid-base combination that results in the liberation of carbon dioxideare used in place of the combination of sodium bicarbonate and citricand tartaric acids, as long as the ingredients were suitable forpharmaceutical use and result in a pH of about 6.0 or higher.

In other embodiments, the formulations described herein, which include acompound described herein, are solid dispersions. In still otherembodiments, the formulations described herein are solid solutions.Solid solutions incorporate a substance together with the active agentand other excipients such that heating the mixture results indissolution of the drug and the resulting composition is then cooled toprovide a solid blend which is further formulated or directly added to acapsule or compressed into a tablet.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compound of Formula (I)-(XV) and GroupA described herein, are further formulated to provide a controlledrelease of the compound of Formula (I)-(XV) and Group A. Controlledrelease refers to the release of the compound of Formula (I)-(XV) andGroup A described herein from a dosage form in which it is incorporatedaccording to a desired profile over an extended period of time.Controlled release profiles include, for example, sustained release,prolonged release, pulsatile release, and delayed release profiles. Incontrast to immediate release compositions, controlled releasecompositions allow delivery of an agent to a subject over an extendedperiod of time according to a predetermined profile. In someembodiments, such release rates provide therapeutically effective levelsof agent for an extended period of time and thereby provide a longerperiod of pharmacologic response while minimizing side effects ascompared to conventional rapid release dosage forms. Such longer periodsof response provide for many inherent benefits that are not achievedwith the corresponding short acting, immediate release preparations.

In some embodiments, the solid dosage forms described herein areformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. In further embodiments, theenteric coated dosage form is a compressed or molded or extrudedtablet/mold (coated or uncoated) containing granules, powder, pellets,beads or particles of the active ingredient and/or other compositioncomponents, which are themselves coated or uncoated. In otherembodiments, the enteric coated oral dosage form is also a capsule(coated or uncoated) containing pellets, beads or granules of the solidcarrier or the composition, which are themselves coated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release is accomplished at some generally predictable location inthe intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is a coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. In some embodiments, coatingsare made from:

Acrylic polymers. In some embodiments, the performance of acrylicpolymers (primarily their solubility in biological fluids) vary based onthe degree and type of substitution. Examples of suitable acrylicpolymers include methacrylic acid copolymers and ammonium methacrylatecopolymers. The Eudragit series E, L, S, RL, RS and NE (Rohm Pharma) areavailable as solubilized in organic solvent, aqueous dispersion, or drypowders. The Eudragit series RL, NE, and RS are insoluble in thegastrointestinal tract but are permeable and are used primarily forcolonic targeting. The Eudragit series E dissolve in the stomach. TheEudragit series L, L-30D and S are insoluble in stomach and dissolve inthe intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. In other embodiments, the performancevaries based on the degree and type of substitution. Cellulose acetatephthalate (CAP) dissolves in pH>about 6. Aquateric (FMC) is an aqueousbased system and is a spray dried CAP psuedolatex with particles <1 μm.In other embodiments, other components in Aquateric include pluronics,Tweens, and acetylated monoglycerides. Other suitable cellulosederivatives include: cellulose acetate trimellitate (Eastman);methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulosephthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); andhydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (ShinEtsu)). In further embodiments, the performance varies based on thedegree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-55S, HP-55F grades are suitable. In other embodiments, theperformance varies based on the degree and type of substitution. Forexample, suitable grades of hydroxypropylmethylcellulose acetatesuccinate include, but are not limited to, AS-LG (LF), which dissolvesat pH about 5, AS-MG (MF), which dissolves at pH about 5.5, and AS-HG(HF), which dissolves at higher pH. These polymers are offered asgranules, or as fine powders for aqueous dispersions.

Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH>about 5, andit is much less permeable to water vapor and gastric fluids.

In some embodiments, the coating contains a plasticizer and possiblyother coating excipients such as colorants, talc, and/or magnesiumstearate. Suitable plasticizers include triethyl citrate (Citroflex 2),triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2),Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributylcitrate, acetylated monoglycerides, glycerol, fatty acid esters,propylene glycol, and dibutyl phthalate. In some embodiments, anioniccarboxylic acrylic polymers contain about 10 to about 25% by weight of aplasticizer, especially dibutyl phthalate, polyethylene glycol, triethylcitrate and triacetin. Conventional coating techniques such as spray orpan coating are employed to apply coatings. The coating thickness mustbe sufficient to ensure that the oral dosage form remains intact untilthe desired site of topical delivery in the intestinal tract is reached.

In some embodiments, colorants, detackifiers, surfactants, antifoamingagents, lubricants (e.g., carnuba wax or PEG) are added to the coatingsbesides plasticizers to solubilize or disperse the coating material, andto improve coating performance and the coated product.

In other embodiments, the formulations described herein, which include acompound of Formula (I)-(XV) and Group A described herein, are deliveredusing a pulsatile dosage form. A pulsatile dosage form is capable ofproviding one or more immediate release pulses at predetermined timepoints after a controlled lag time or at specific sites. In furtherembodiments, pulsatile dosage forms are administered using a variety ofpulsatile formulations.

Examples of such delivery systems include, e.g., polymer-based systems,such as polylactic and polyglycolic acid, polyanhydrides andpolycaprolactone; porous matrices, nonpolymer-based systems that arelipids, including sterols, such as cholesterol, cholesterol esters andfatty acids, or neutral fats, such as mono-, di- and triglycerides;hydrogel release systems; silastic systems; peptide-based systems; waxcoatings, bioerodible dosage forms, compressed tablets usingconventional binders and the like.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds described herein, e.g. compounds ofFormula (I)-(XV) and Group A, and at least one dispersing agent orsuspending agent for oral administration to a subject. In someembodiments, the formulations are a powder and/or granules forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained.

In some embodiments, liquid formulation dosage forms for oraladministration are aqueous suspensions selected from the groupincluding, but not limited to, pharmaceutically acceptable aqueous oraldispersions, emulsions, solutions, elixirs, gels, and syrups.

In other embodiments, the aqueous suspensions and dispersions describedherein remain in a homogenous state, as defined in The USP Pharmacists'Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. Thehomogeneity should be determined by a sampling method consistent withregard to determining homogeneity of the entire composition. In oneembodiment, an aqueous suspension is re-suspended into a homogenoussuspension by physical agitation lasting less than about 1 minute. Inanother embodiment, an aqueous suspension is re-suspended into ahomogenous suspension by physical agitation lasting less than about 45seconds. In yet another embodiment, an aqueous suspension isre-suspended into a homogenous suspension by physical agitation lastingless than about 30 seconds. In still another embodiment, no agitation isnecessary to maintain a homogeneous aqueous dispersion.

In some embodiments, the pharmaceutical formulations described hereinare self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, in other embodiments, water orthe aqueous phase is added just prior to administration, which ensuresstability of an unstable or hydrophobic active ingredient. Thus, theSEDDS provides an effective delivery system for oral and parenteraldelivery of hydrophobic active ingredients. In further embodiments,SEDDS provides improvements in the bioavailability of hydrophobic activeingredients.

It is to be appreciated that there is overlap between the above-listedadditives used in the aqueous dispersions or suspensions describedherein, since a given additive is often classified differently bydifferent practitioners in the field, or is commonly used for any ofseveral different functions. Thus, in other embodiments, theabove-listed additives are taken as merely exemplary, and not limiting,of the types of additives that are included in formulations describedherein.

In some embodiments, formulations that include a compound describedherein, are prepared according to these and other techniques areprepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, fluorocarbons, and/or other solubilizing ordispersing agents. In other embodiments, are compositions andformulations prepared with suitable nontoxic pharmaceutically acceptableingredients. In further embodiments, these ingredients are found inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005. Thechoice of suitable carriers is highly dependent upon the exact nature ofthe nasal dosage form desired, e.g., solutions, suspensions, ointments,or gels. Nasal dosage forms generally contain large amounts of water inaddition to the active ingredient. Minor amounts of other ingredientssuch as pH adjusters, emulsifiers or dispersing agents, preservatives,surfactants, gelling agents, or buffering and other stabilizing andsolubilizing agents may also be present. In other embodiments, the nasaldosage form is isotonic with nasal secretions.

In some embodiments, for administration by inhalation, the compoundsdescribed herein are in a form as an aerosol, a mist or a powder.Pharmaceutical compositions described herein are conveniently deliveredin the form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Infurther embodiments, are pressurized aerosols, wherein the dosage unitis determined by providing a valve to deliver a metered amount. Capsulesand cartridges of, such as, by way of example only, gelatin for use inan inhaler or insufflator are formulated containing a powder mix of thecompound described herein and a suitable powder base such as lactose orstarch.

In other embodiments, are buccal formulations that include compoundsdescribed herein are administered using a variety of formulations. Insome embodiments, the buccal dosage forms described herein furtherinclude a bioerodible (hydrolysable) polymeric carrier that also servesto adhere the dosage form to the buccal mucosa. The buccal dosage formis fabricated so as to erode gradually over a predetermined time period,wherein the delivery of the compound is provided essentially throughout.Buccal drug delivery, avoids the disadvantages encountered with oraldrug administration, e.g., slow absorption, degradation of the activeagent by fluids present in the gastrointestinal tract and/or first-passinactivation in the liver. With regard to the bioerodible (hydrolysable)polymeric carrier, it will be appreciated that virtually any suchcarrier is used, so long as the desired drug release profile is notcompromised, and the carrier is compatible with the compound of Formula(I)-(XV) and Group A described herein, and any other components that arepresent in the buccal dosage unit. Generally, the polymeric carriercomprises hydrophilic (water-soluble and water-swellable) polymers thatadhere to the wet surface of the buccal mucosa. Examples of polymericcarriers useful herein include acrylic acid polymers and co, e.g., thoseknown as “carbomers” (Carbopol®, which are obtained from B.F. Goodrich,is one such polymer). In further embodiments are components incorporatedinto the buccal dosage forms described herein include, but are notlimited to, disintegrants, diluents, binders, lubricants, flavoring,colorants, preservatives, and the like. In yet further embodiments, arebuccal or sublingual administration, wherein the compositions take theform of tablets, lozenges, or gels formulated in a conventional manner.

In further embodiments, are transdermal formulations described hereinadministered using a variety of devices.

In other embodiments the transdermal dosage forms described hereinincorporate certain pharmaceutically acceptable excipients. In oneembodiment, the transdermal formulations described herein include atleast three components: (1) a formulation of a compound of Formula(I)-(XV) and Group A; (2) a penetration enhancer; and (3) an aqueousadjuvant. In addition, transdermal formulations include additionalcomponents such as, but not limited to, gelling agents, creams andointment bases, and the like. In some embodiments, the transdermalformulation further includes a woven or non-woven backing material toenhance absorption and prevent the removal of the transdermalformulation from the skin. In other embodiments, the transdermalformulations described herein maintains a saturated or supersaturatedstate to promote diffusion into the skin.

In other embodiments, formulations suitable for transdermaladministration of compounds described herein employ transdermal deliverydevices and transdermal delivery patches and are lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. Such patches are constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents. Still further, in someembodiments, transdermal delivery of the compounds described herein areaccomplished by means of iontophoretic patches and the like.Additionally, in other embodiments, transdermal patches providecontrolled delivery of the compound of Formula (I)-(XV) and Group Adescribed herein.

In further embodiments, the rate of absorption is slowed by usingrate-controlling membranes or by trapping the compound within a polymermatrix or gel. Conversely, in yet further embodiments, absorptionenhancers are used to increase absorption. An absorption enhancer orcarrier includes absorbable pharmaceutically acceptable solvents toassist passage through the skin. For example, transdermal devices are inthe form of a bandage comprising a backing member, a reservoircontaining the compound optionally with carriers, optionally a ratecontrolling barrier to deliver the compound to the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

In further embodiments, formulations suitable for intramuscular,subcutaneous, or intravenous injection include physiologicallyacceptable sterile aqueous or non-aqueous solutions, dispersions,suspensions or emulsions, and sterile powders for reconstitution intosterile injectable solutions or dispersions. Examples of suitableaqueous and non-aqueous carriers, diluents, solvents, or vehiclesincluding water, ethanol, polyols (propyleneglycol, polyethylene-glycol,glycerol, cremophor and the like), suitable mixtures thereof, vegetableoils (such as olive oil) and injectable organic esters such as ethyloleate. In some embodiments, proper fluidity is maintained, for example,by the use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants. In further embodiments, formulations suitable forsubcutaneous injection also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms is ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form are brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

In some embodiments, are intravenous injections, compounds formulated inaqueous solutions; in some embodiments, in physiologically compatiblebuffers such as Hank's solution, Ringer's solution, or physiologicalsaline buffer. For transmucosal administration, penetrants appropriateto the barrier to be permeated are used in the formulation For otherparenteral injections, appropriate formulations may include aqueous ornonaqueous solutions; in other embodiments, with physiologicallycompatible buffers or excipients.

In some embodiments, parenteral injections involve bolus injection orcontinuous infusion. In other embodiments, formulations for injectionare presented in unit dosage form, e.g., in ampoules or in multi-dosecontainers, with an added preservative. In some embodiments, thepharmaceutical compositions described herein are in a form suitable forparenteral injection as a sterile suspensions, solutions or emulsions inoily or aqueous vehicles, and contain formulatory agents such assuspending, stabilizing and/or dispersing agents. Pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. Additionally, in otherembodiments, suspensions of the active compounds are prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. In furtherembodiments, aqueous injection suspensions contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. In some embodiments, the suspensionalso contains suitable stabilizers or agents which increase thesolubility of the compounds to allow for the preparation of highlyconcentrated solutions. In other embodiments, the active ingredient isin powder form for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

In certain embodiments, delivery systems for pharmaceutical compoundsare employed, such as, for example, liposomes and emulsions. In certainembodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein are administeredtopically and are formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,medicated sticks, balms, creams or ointments. Such pharmaceuticalcompounds contain for example, solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

In some embodiments, the compounds described herein are also formulatedin rectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG, and the like. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter is first melted.

Generally, an agent, such as a compound of Formula (I)-(XV) and Group A,is administered in an amount effective for amelioration of, orprevention of the development of symptoms of, the disease, condition ordisorder (i.e., a therapeutically effective amount). Thus, in someembodiments, a therapeutically effective amount is an amount that iscapable of at least partially preventing or reversing a disease,condition or disorder. In other embodiments, the dose required to obtainan effective amount varies depending on the agent, formulation, disease,condition or disorder, and individual to whom the agent is administered.

In other embodiments, determination of effective amounts also involvesin vitro assays in which varying doses of agent are administered tocells in culture and the concentration of agent effective forameliorating some or all symptoms is determined in order to calculatethe concentration required in vivo. Effective amounts are also based onin vivo animal studies.

In other embodiments, an agent is administered prior to, concurrentlywith and subsequent to the appearance of symptoms of a disease,condition or disorder. In some embodiments, an agent is administered toa subject with a family history of the disease, condition or disorder,or who has a phenotype that indicates a predisposition to a disease,condition or disorder, or who has a genotype which predisposes thesubject to the disease, condition or disorder.

In some embodiments, the particular delivery system used depends on anumber of factors, including, for example, the intended target and theroute of administration, e.g., local or systemic. Targets for deliveryare specific cells which are causing or contributing to a disease,condition or disorder, including, for example, cells that have alteredintracellular calcium or calcium dysregulation or dyshomeostasis, andcells that do not have altered intracellular calcium but that in someembodiments, have some alteration, defect or deficiency that is, atleast in part, compensated, counteracted, reversed or alleviated oreliminated by altering intracellular calcium of the cell. Particularcells include, for example, immune cells (e.g., lymphocytes, T cells, Bcells, white blood cells), fibroblasts (or cells derived from afibroblast), epidermal, dermal or skin cells (e.g., a keratinocytes),blood cells, kidney or renal cells (e.g., mesangial cells), muscle cells(e.g., a smooth muscle cell such as an airway (tracheal or bronchial)smooth muscle cell) and exocrine or secretory (e.g., salivary, includingparotid acinar and submandibular gland) cells. For example, in someembodiments, a target cell is a resident or infiltrating cells in thelungs or airways that contribute to an asthmatic illness or disease,resident or infiltrating cells in the nervous system contributing to aneurological, neurodegenerative or demyelinating disease, condition ordisorder, resident or infiltrating cells involved in rejection of akidney graft, grafted cells that when activated lead tograft-versus-host disease, resident or infiltrating cells involved inrejection of a kidney graft, resident or infiltrating cells, activationof which contributes to inflammation, e.g., in arthritis, resident orinfiltrating cells in the kidney or renal system (e.g., mesangial cells)involved in neuropathy and glomerulonephritis and resident orinfiltrating cells in exocrine glands (e.g., salivary and lacrimalglands) involved in autoimmune disorders (e.g., Sjogren's disease). Insome embodiments, an agent is coupled to an antibody, ligand to a cellsurface receptor or a toxin, or is contained in a particle that isselectively internalized into cells, e.g., liposomes or a virus in whichthe viral receptor binds specifically to a certain cell type, or a viralparticle lacking the viral nucleic acid, or are administered locally.

Examples of Methods of Dosing and Treatment Regimens

In some embodiments, the compounds described herein are used in thepreparation of medicaments for the modulation of intracellular calcium,or for the treatment of diseases, disorders or conditions that wouldbenefit, at least in part, from modulation of intracellular calcium. Inaddition, a method for treating any of the diseases, disorders orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein, or a pharmaceutically acceptablesalt, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidsubject.

In other embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In therapeutic applications, the compositions areadministered to a patient already suffering from a disease, disorder orcondition, in an amount sufficient to cure or at least partially arrestthe symptoms of the disease, disorder or condition. Amounts effectivefor this use will depend on the severity and course of the disease,disorder or condition, previous therapy, the patient's health status,weight, and response to the drugs, and the judgment of the treatingphysician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In some embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds isadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In other embodiments, wherein the patient's status does improve, uponthe doctor's discretion the administration of the compounds are givencontinuously; alternatively, the dose of drug being administered istemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). In other embodiments, the length of thedrug holiday varies between about 2 days and about 1 year, including byway of example only, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about 7 days, about 10 days, about 12 days, about 15days, about 20 days, about 28 days, about 35 days, about 50 days, about70 days, about 100 days, about 120 days, about 150 days, about 180 days,about 200 days, about 250 days, about 280 days, about 300 days, about320 days, about 350 days, or about 365 days. In some embodiments, thedose reduction during a drug holiday is from about 10% to about 100%,including, by way of example only, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in other embodiments,the dosage or the frequency of administration, or both, is reduced, as afunction of the symptoms, to a level at which the improved disease,disorder or condition is retained. In other embodiments, patients,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms.

In other embodiments, the amount of a given agent varies depending uponfactors such as the particular compound, disease, disorder or conditionand its severity, the identity (e.g., weight) of the subject or host inneed of treatment, but is nevertheless determined in a manner accordingto the particular circumstances surrounding the case, including, e.g.,the specific agent being administered, the route of administration, thecondition being treated, and the subject or host being treated. In someembodiments, doses employed for adult human treatment are typically inthe range of about 0.02 to about 5000 mg per day, in other embodiments,about 1 to about 1500 mg per day. In further embodiments, the desireddose is conveniently presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In other embodiments, the pharmaceutical composition described herein isin unit dosage forms suitable for single administration of precisedosages. In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or more compound. In furtherembodiments, the unit dosage is in the form of a package containingdiscrete quantities of the formulation. Non-limiting examples arepackaged tablets or capsules, and powders in vials or ampoules. In otherembodiments, aqueous suspension compositions are packaged in single-dosenon-reclosable containers. In further embodiments, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition. By way of example only, formulationsfor parenteral injection are presented in unit dosage form, whichinclude, but are not limited to ampoules, or in multi-dose containers,with an added preservative.

The daily dosages appropriate for the compounds described hereindescribed herein are from about 0.01 mg/kg to about 20 mg/kg. In oneembodiment, the daily dosages are from about 0.1 mg/kg to about 10mg/kg. An indicated daily dosage in the larger mammal, including, butnot limited to, humans, is in the range from about 0.5 mg to about 1000mg, conveniently administered in a single dose or in divided doses,including, but not limited to, up to four times a day or in extendedrelease form. Suitable unit dosage forms for oral administration includefrom about 1 to about 500 mg active ingredient. In one embodiment, theunit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about500 mg. The foregoing ranges are merely suggestive, as the number ofvariables in regard to an individual treatment regime is large, andconsiderable excursions from these recommended values are not uncommon.In some embodiments, such dosages are altered depending on a number ofvariables, not limited to the activity of the compound used, thedisease, disorder or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease, disorder or condition being treated, and the judgment ofthe practitioner.

In further embodiments, toxicity and therapeutic efficacy of suchtherapeutic regimens are determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, including, but notlimited to, the determination of the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between the toxic and therapeuticeffects is the therapeutic index and it are expressed as the ratiobetween LD₅₀ and ED₅₀. In other embodiments, are compounds exhibitinghigh therapeutic indices. In other embodiments, the data obtained fromcell culture assays and animal studies are used in formulating a rangeof dosage for use in human. In some other embodiments, the dosage ofsuch compounds lies within a range of circulating concentrations thatinclude the ED₅₀ with minimal toxicity. In further embodiments, thedosage varies within this range depending upon the dosage form employedand the route of administration utilized.

Combination Treatments

In other embodiments, the compounds of Formula (I)-(XV) and Group A, andcompositions thereof, are also used in combination with othertherapeutic agents that are selected for their therapeutic value for thecondition to be treated. In general, the compositions described hereinand, in embodiments where combinational therapy is employed, otheragents do not have to be administered in the same pharmaceuticalcomposition, and in some embodiments, because of different physical andchemical characteristics, have to be administered by different routes.

In certain instances, it is appropriate to administer at least onecompound of Formula (I)-(XV) and Group A described herein in combinationwith another therapeutic agent. By way of example only, if one of theside effects experienced by a patient upon receiving one of thecompounds herein, such as a compound of Formula (I)-(XV) and Group A, isnausea, then it is appropriate to administer an anti-nausea agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein is enhanced by administration of an adjuvant (i.e., by itself theadjuvant has minimal therapeutic benefit, but in combination withanother therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, by way of example only, the benefitexperienced by a patient is increased by administering one of thecompounds described herein with another therapeutic agent (which alsoincludes a therapeutic regimen) that also has therapeutic benefit. Inany case, in other embodiments, regardless of the disease, disorder orcondition being treated, the overall benefit experienced by the patientis simply be additive of the two therapeutic agents or the patientexperiences a synergistic benefit.

In other embodiments, the particular choice of compounds used dependsupon the diagnosis of the attending physicians and their judgment of thecondition of the patient and the appropriate treatment protocol. Infurther embodiments, the compounds are administered concurrently (e.g.,simultaneously, essentially simultaneously or within the same treatmentprotocol) or sequentially, depending upon the nature of the disease,disorder, or condition, the condition of the patient, and the actualchoice of compounds used.

In some embodiments, therapeutically-effective dosages vary when thedrugs are used in treatment combinations. Combination treatment furtherincludes periodic treatments that start and stop at various times toassist with the clinical management of the patient.

In some embodiments, combination therapies described herein, dosages ofthe co-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease, disorder orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein is administered either simultaneously with the biologicallyactive agent(s), or sequentially. In some embodiments, if administeredsequentially, the attending physician decides on the appropriatesequence of administering protein in combination with the biologicallyactive agent(s).

In some embodiments, the multiple therapeutic agents (one of which is acompound of Formula (I)-(XV) and Group A described herein) areadministered in any order or even simultaneously. In other embodiments,if simultaneously, the multiple therapeutic agents are provided in asingle, unified form, or in multiple forms (by way of example only,either as a single pill or as two separate pills). In other embodiments,one of the therapeutic agents are given in multiple doses, or both aregiven as multiple doses. If not simultaneous, the timing between themultiple doses vary from more than zero weeks to less than about fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors. These factors include thedisorder, disease or condition from which the subject suffers, as wellas the age, weight, sex, diet, and medical condition of the subject.Thus, in other embodiments, the dosage regimen actually employed varieswidely and therefore can deviate from the dosage regimens set forthherein.

In other embodiments, the pharmaceutical agents who make up thecombination therapy disclosed herein are in a combined dosage form or inseparate dosage forms intended for substantially simultaneousadministration. In other embodiments, the pharmaceutical agents thatmake up the combination therapy are also administered sequentially, witheither therapeutic compound being administered by a regimen calling fortwo-step administration. In yet other embodiments, the two-stepadministration regimen calls for sequential administration of the activeagents or spaced-apart administration of the separate active agents. Infurther embodiments, the time period between the multiple administrationsteps range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. In other embodiments, circadian variation of thetarget molecule concentration also determines the optimal dose interval.

In addition, the compounds described herein also are used in combinationwith procedures that in some embodiments, provide additional orsynergistic benefit to the patient. By way of example only, patients areexpected to find therapeutic and/or prophylactic benefit in the methodsdescribed herein, wherein pharmaceutical composition of a compounddisclosed herein and/or combinations with other therapeutics arecombined with genetic testing to determine whether that individual is acarrier of a mutant gene that is known to be correlated with certaindiseases or conditions.

In further embodiments, the compounds described herein and combinationtherapies are administered before, during or after the occurrence of adisease, disorder or condition, and the timing of administering thecomposition containing a compound varies. Thus, for example, thecompounds are used as a prophylactic and are administered continuouslyto subjects with a propensity to develop conditions, disorders ordiseases in order to prevent the occurrence of the disease, disorder orcondition. In other embodiments, the compounds and compositions areadministered to a subject during or as soon as possible after the onsetof the symptoms. In other embodiments, the administration of thecompounds are initiated within the first 48 hours of the onset of thesymptoms, in some embodiments, within the first 48 hours of the onset ofthe symptoms, in yet other embodiments within the first 6 hours of theonset of the symptoms, and in other embodiments within 3 hours of theonset of the symptoms. In further embodiments, the initialadministration is via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over about 5 minutesto about 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. In other embodiments, a compoundis administered as soon as is practicable after the onset of a disease,disorder or condition is detected or suspected, and for a length of timenecessary for the treatment of the disease, such as, for example, fromabout 1 day to about 3 months. In other embodiments, the length oftreatment varies for each subject, and the length is determined usingthe known criteria. For example, the compound or a formulationcontaining the compound is administered for at least 2 weeks, in someembodiments about 1 month to about 5 years.

Inhibitors of SOCE

In one aspect, compounds of Formula (I)-(XV) and Group A areadministered or used in conjunction with other inhibitors of SOCE. Inone embodiment, the inhibitors of SOCE are non-selective inhibitors. Inone embodiment, the inhibitors of SOCE are selective inhibitors.

A variety of inhibitors of SOCE have been described. Inhibitors of SOCEinclude:

a) Cations, which include lanthanide cations, such as for example, Gd³⁺,La³⁺;

b) P-450 inhibitors, which include econazole, miconazole, clotrimazole,ketoconazole;

c) Cyclooxygenase inhibitors, which include niflumic acid, flufenamicacid, tenidap;

d) Lipoxygenase inhibitors, which include nordihydroguaiaretic acid,eicosatetraynoic acid;

e) Compounds that are channel blockers, which include SK&F 96365,SC38249, LU52396, L-651,582, tetrandrine, 2-APB;

f) Compounds that inhibit SOCE not by an action on the SOC channelsthemselves, which include U73122 (phospholipase C inhibitor), wortmannin(phosphatidylinositol kinase inhibitor).

Some of these inhibitors of SOCE have non-specific actions and/ormultiple modes of action that contribute to the inhibition of SOCE,which include blocking the pore of the SOC channel (Channel blockers),inhibition of mitochondrial ATP synthesis that appears to support SOCE,disturbances of cytoplasmic pH (, as well as inhibiting the activationof SOC channels.

Immunosuppressants

In one embodiment, compounds of Formula (I)-(XV) and Group A areadministered as single agents in immunosuppressive therapy to reduce,inhibit, or prevent activity of the immune system. Immunosuppressivetherapy is clinically used to: prevent the rejection of transplantedorgans and tissues (e.g. bone marrow, heart, kidney, liver); treatmentof autoimmune diseases or diseases that are most likely of autoimmuneorigin (e.g. rheumatoid arthritis, myasthenia gravis, systemic lupuserythematosus, Crohn's disease, and ulcerative colitis); and treatmentof some other non-autoimmune inflammatory diseases (e.g. long termallergic asthma control).

In some embodiments, a compound of Formula (I)-(XV) and Group A isadministered with other immunosuppressants selected from among:Calcineurin inhibitors (such as, but not limited to, cyclosporin,tacrolimus); mTOR inhibitors (such as, but not limited to, sirolimus,everolimus); anti-proliferatives (such as, but not limited to,azathioprine, mycophenolic acid); corticosteroids (such as, but notlimited to, prednisone, cortisone acetate, prednisolone,methylprednisolone, dexamethasone, betamethasone, triamcinolone,beclometasone, fludrocortisone acetate, deoxycorticosterone acetate,aldosterone, hydrocortisone); antibodies (such as, but not limited to,monoclonal anti-IL-2Rα receptor antibodies (basiliximab, daclizumab),polyclonal anti-T-cell antibodies (anti-thymocyte globulin (ATG),anti-lymphocyte globulin (ALG))).

Other immunosuppressants include, but are not limited to:glucocorticoids (alclometasone, aldosterone, amcinonide, beclometasone,betamethasone, budesonide, ciclesonide, clobetasol, clobetasone,clocortolone, cloprednol, cortisone, cortivazol, deflazacort,deoxycorticosterone, desonide, desoximetasone, desoxycortone,dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone,Fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone,fluperolone, fluprednidene, fluticasone, formocortal, halcinonide,halometasone, hydrocortisone/cortisol, hydrocortisone aceponate,hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,medrysone, meprednisone, methylprednisolone, methylprednisoloneaceponate, mometasone furoate, paramethasone, prednicarbate, prednisone,prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone,ulobetasol), cyclophosphamide, nitrosoureas, cisplatin, carboplatin,oxaliplatin, methotrexate, azathioprine, mercaptopurine, pyrimidineanalogues, protein synthesis inhibitors, methotrexate, azathioprine,mercaptopurine, dactinomycin, anthracyclines, mitomycin C, bleomycin,mithramycin, Atgam^((R)), Thymoglobuline®, OKT3®, basiliximab,daclizumab, cyclosporin, tacrolimus, sirolimus, Interferons (IFN-β,IFN-γ), opioids, TNF binding proteins (infliximab, etanercept,adalimumab, golimumab), mycophenolic acid, mycophenolate mofetil,FTY720, as well as those listed in U.S. Pat. No. 7,060,697.

Agents for Treating Autoimmune Diseases, Inflammatory Diseases

In some embodiments, where the subject is suffering from or at risk ofsuffering from an autoimmune disease, disorder or condition, or aninflammatory disease, disorder or condition, a compound of Formula(I)-(XV) and Group A is administered in any combination with one or moreof the following therapeutic agents: immunosuppressants (e.g.,tacrolimus, cyclosporin, rapamicin, methotrexate , cyclophosphamide,azathioprine, mercaptopurine, mycophenolate, or FTY720), glucocorticoids(e.g., prednisone, cortisone acetate, prednisolone, methylprednisolone,dexamethasone, betamethasone, triamcinolone, beclometasone,fludrocortisone acetate, deoxycorticosterone acetate, aldosterone),non-steroidal anti-inflammatory drugs (e.g., salicylates, arylalkanoicacids, 2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs,or sulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,etoricoxib, lumiracoxib, celecoxib, or rofecoxib), leflunomide, goldthioglucose, gold thiomalate, aurofin, sulfasalazine,hydroxychloroquinine, minocycline, TNF-α binding proteins (e.g.,infliximab, etanercept, or adalimumab), abatacept, anakinra,interferon-β, interferon-γ, interleukin-2, antileukotrienes,theophylline, or anticholinergics.

In one embodiment, compounds of Formula (I)-(XV) and Group A describedherein, are administered in combination with inhibitors ofNFAT-calcineurin pathway. In one embodiment, the inhibitors ofNFAT-calcineurin pathway include, but are not limited to, Cyclosporin A(CsA) and tacrolimus (FK506).

In one embodiment, a compound of Formula (I)-(XV) and Group A, orcompositions and medicaments that include a compound of Formula (I)-(XV)and Group A, are administered to a patient in combination with ananti-inflammatory agent including, but not limited to, non-steroidalanti-inflammatory drugs (NSAIDs) and corticosteroids (glucocorticoids).

NSAIDs include, but are not limited to: aspirin, salicylic acid,gentisic acid, choline magnesium salicylate, choline salicylate, cholinemagnesium salicylate, choline salicylate, magnesium salicylate, sodiumsalicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium,fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolactromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin,sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid,piroxicam, meloxicam, COX-2 specific inhibitors (such as, but notlimited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,lumiracoxib, CS-502, JTE-522, L-745,337 and NS398).

Combinations with NSAIDs, which are selective COX-2 inhibitors, arecontemplated herein. Such compounds include, but are not limited tothose disclosed in U.S. Pat. Nos. 5,474,995 ; 5,861,419 ; 6,001,843 ;6,020,343 , 5,409,944 ; 5,436,265 ; 5,536,752 ; 5,550,142 ; 5,604,260 ;5,698,584 ; 5,710,140 ; U,S. Pat. Nos. WO 94/15932 ; 5,344,991 ;5,134,142 ; 5,380,738 ; 5,393,790 ; 5,466,823 ; 5,633,272 ; 5,932,598and U.S. Pat. No. 6,313,138; the disclosure of NSAIDs which are hereinincorporated by reference.

Compounds that have been described as selective COX-2 inhibitors and aretherefore useful in the methods or pharmaceutical compositions describedherein include, but are not limited to, celecoxib, rofecoxib,lumiracoxib, etoricoxib, valdecoxib, and parecoxib, or apharmaceutically acceptable salt thereof.

Corticosteroids, include, but are not limited to: betamethasone,prednisone, alclometasone, aldosterone, amcinonide, beclometasone,betamethasone, budesonide, ciclesonide, clobetasol, clobetasone,clocortolone, cloprednol, cortisone, cortivazol, deflazacort,deoxycorticosterone, desonide, desoximetasone, desoxycortone,dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone,fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone,fluperolone, fluprednidene, fluticasone, formocortal, halcinonide,halometasone, hydrocortisone/cortisol, hydrocortisone aceponate,hydrocortisone buteprate, hydrocortisone butyrate, loteprednol,medrysone, meprednisone, methylprednisolone, methylprednisoloneaceponate, mometasone furoate, paramethasone, prednicarbate,prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, andulobetasol.

Other agents used as anti-inflammatories include those disclosed in U.S.patent publication 2005/0227929, the disclosure of anti-inflammatorieswhich is herein incorporated by reference.

Some commercially available anti-inflammatories include, but are notlimited to: Arthrotec® (diclofenac and misoprostol), Asacol®(5-aminosalicyclic acid), Salofalk® (5-aminosalicyclic acid), Auralgan®(antipyrine and benzocaine), Azulfidine® (sulfasalazine), Daypro®(oxaprozin), Lodine® (etodolac), Ponstan® (mefenamic acid), Solumedrol®(methylprednisolone), Bayer® (aspirin), Bufferin® (aspirin), Indocin®(indomethacin), Vioxx® (rofecoxib), Celebrex® (celecoxib), Bextra®(valdecoxib), Arcoxia® (etoricoxib), Prexige® (lumiracoxib), Advil®,Motrin® (ibuprofen), Voltaren® (diclofenac), Orudis® (ketoprofen),Mobic® (meloxicam), Relafen® (nabumetone), Aleve®, Naprosyn® (naproxen),Feldene® (piroxicam).

In one embodiment, compounds of Formula (I)-(XV) and Group A areadministered in combination with leukotriene receptor antagonistsincluding, but are not limited to, BAY u9773 (see EP 00791576; published27 Aug. 1997), DUO-LT (Tsuji et al, Org. Biomol. Chem., 1, 3139-3141,2003), zafirlukast (Accolate®), montelukast (Singulair®), prankulast(Onon®), and derivatives or analogs thereof.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. In some embodiments,such kits include a carrier, package, or container that iscompartmentalized to receive one or more containers such as vials,tubes, and the like, each of the container(s) including one of theseparate elements to be used in a method described herein. Suitablecontainers include, for example, bottles, vials, syringes, and testtubes. In other embodiments, the containers are formed from a variety ofmaterials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.A wide array of formulations of the compounds and compositions providedherein are contemplated as are a variety of treatments for any disease,disorder, or condition that would benefit by inhibition of CRAC channelactivity.

For example, in some embodiments, the container(s) includes one or morecompounds described herein, optionally in a composition or incombination with another agent as disclosed herein. The container(s)optionally have a sterile access port (for example the container is anintravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle). Such kits optionally comprising a compoundwith an identifying description or label or instructions relating to itsuse in the methods described herein.

In some other embodiments, a kit includes one or more additionalcontainers, each with one or more of various materials (such asreagents, optionally in concentrated form, and/or devices) desirablefrom a commercial and user standpoint for use of a compound describedherein. Non-limiting examples of such materials include, but not limitedto, buffers, diluents, filters, needles, syringes; carrier, package,container, vial and/or tube labels listing contents and/or instructionsfor use, and package inserts with instructions for use. In otherembodiments, a set of instructions is also included.

In further embodiments, is a label on or associated with the container.In other embodiments, the label is on a container when letters, numbersor other characters forming the label are attached, molded or etchedinto the container itself; a label is associated with a container whenit is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In some embodiments, a label isused to indicate that the contents are to be used for a specifictherapeutic application. In yet other embodiments, the label alsoindicates directions for use of the contents, such as in the methodsdescribed herein.

In certain embodiments, the pharmaceutical compositions are presented ina pack or dispenser device which contains one or more unit dosage formscontaining a compound provided herein. In other embodiments, the packcontains metal or plastic foil, such as a blister pack. In otherembodiments, the pack or dispenser device is accompanied by instructionsfor administration. In still other embodiments, the pack or dispenseralso accompanied with a notice associated with the container in formprescribed by a governmental agency regulating the manufacture, use, orsale of pharmaceuticals, which notice is reflective of approval by theagency of the form of the drug for human or veterinary administration.Such notice, for example, is the labeling approved by the U.S. Food andDrug Administration for prescription drugs, or the approved productinsert. Compositions containing a compound provided herein formulated ina compatible pharmaceutical carrier are also prepared, placed in anappropriate container, and labeled for treatment of an indicatedcondition.

Assays

In some embodiments, several techniques are used to evaluate storeoperated calcium entry and calcium signaling in cells. Such techniquesinclude, but are not limited to, patch clamp electrophysiology(measurement of calcium ions or other ions across cell membranes, suchas plasma membranes), capacitance measurements (allows exocytosis to befollowed at the level of single cells), calcium imaging usingfluorescent dyes allows patterns of calcium movement within thecytoplasm to be tracked, fluorescence resonance energy transfer (FRET)enables protein-protein interactions to be evaluated, and molecularbiology methods allow for the manipulation of the levels of expressionof proteins of interest.

In other embodiments, a wide variety of assay methods are used toexamine the modulation of intracellular calcium by compounds of Formula(I)-(XV) and Group A. Such assays include in vitro cell based assays aswell as in vivo animal models. In some embodiments, are assays thatdetect, monitor or measure an effect on intracellular calcium, includingcalcium entry-mediated events. Such assays include, but are not limitedto, assays monitoring, measuring and/or detecting intracellular calciumlevels, modulation of calcium levels, and movement of calcium into, outof or within cells and intracellular organelles. In other embodimentsare assays which also include monitoring, measuring and/or detectingcalcium entry-mediated events and molecules involved in calciumentry-mediated events such as, but not limited to, signal transductionmolecules, transcription factors, secreted molecules and other moleculesthat are affected by changes in calcium homeostasis. Assays include, butare not limited to, those described herein and those described in USpatent publication no. 2007/0031814 and WO 07/081,804, hereinincorporated by reference.

Cells and Cell Models

For in vitro testing of the modulation of intracellular calcium bycompounds of Formula (I)-(XV) and Group A, a wide variety of cell typesfor such assays are available. In one embodiment, the cell is one inwhich store-operated calcium entry occurs or that is manipulated suchthat store-operated calcium entry occurs in the cell. In otherembodiments, the cell contains one or more proteins involved inmodulating intracellular calcium (and, in particular, is involved in,participates in and/or provides for store-operated calcium entry,movement of calcium into, out of or within an intracellular organelle orcalcium store, modulation of calcium levels in an intracellularorganelle or calcium store (e.g., endoplasmic reticulum) and/or calciumbuffering), such as those provided herein. In further embodiments, theprotein(s) include a STIM proteins (including STIM1, STIM2, DSTIM andCSTIM protein) and/or Orai proteins (Orai1, Orai2, Orai3). The cell mayendogenously express the protein(s) or recombinantly express theprotein(s).

In some embodiments, cells for use in the methods are of any species. Inone embodiment, the cells are eukaryotic cells. In one embodiment, thecells are yeast, insect (e.g., Drosophila or Anopheles), or mammaliancells. Mammalian cells include, but are not limited to, rodent (e.g.,mouse, rat and hamster), primate, monkey, dog, bovine, rabbit and humancells. A variety of cell types are used in the methods, including, forexample, neuronal, nervous system, brain, immune system cells, e.g., Tlymphocytes and B cells, primary cells, blood and hematopoietic cells,stromal cells, myeloid cells, lymphoid cells, and a variety of tumor andcancer cells. Particular cells include Drosophila Schneider 2 or S2cells, human embryonic kidney (HEK293) cells, rat basophilic leukemia(RBL-2H3) cells, Jurkat cells, epithelial cells, rhabdomyosarcoma cells,rhabdoid cells, retinoblastoma cells, neuroepithelioma cells,neuroblastoma cells, osteosarcoma cells, fibroblasts, bone marrow stromacells, erythroleukemia cells and lymphoblast cells. Other cell linesinclude HEK 293 and 293T, CHO (including CHO-K1), LTK-, N2A, H6, andHGB. Many such cells and cell lines are available through celldepositories such as, for example, the American Type Culture Collection(ATCC, Manassas, Va.). In further embodiments, primary cells areobtained by isolation from tissue sources. The generation, maintenanceand use of such cells and cell lines is well known.

In other embodiments, cells from a known cell line are used, such asneuroblastoma SH-SY5Y cells, pheochromocytoma PC12 cells, neuroblastomaSK-N-BE(2)C or SK-N-SH cells, human SK-N-MC neuroepithelioma cells,SMS-KCNR cells, human LAN-5 neuroblastoma cells, human GI-CA-Nneuroblastoma cells, human GOTO neuroblastoma cells, mouse Neuro 2a(N2A) neuroblastoma cells and/or human IMR 32 neuroblastoma cells,chronic myeloid leukemia cells (e.g., human K562 cells), promyelocyticleukemia cells (e.g., HL60 cells) and histiocytic lymphoma cells (e.g.,U937 cells), Burkitt's lymphoma cells (e.g., CA46 cells), B-cells (e.g.,NALM6), acute lymphoblastic leukemia cells (e.g., MOLT4 cells), T cells(e.g. Jurkat cells) and early T-ALL (e.g., DU528) cells.

The choice of a cell for use in an in vitro assay to test the modulationof intracellular calcium by compounds of Formula (I)-(XV) and Group Ainvolve several considerations, including, for example, a particularprotein that is being used in the method and a particular aspect oractivity of intracellular calcium modulation that is being monitored orassessed in the method.

In one embodiment, the modulation of intracellular calcium by a compoundof Formula (I)-(XV) and Group A is examined by monitoring or assessingthe effect on store-operated calcium entry. Cells typically used in suchmethods exhibit store-operated calcium entry either naturally or throughmanipulation of the cells. In other embodiments, cells that endogenouslyexhibit store-operated calcium entry include some excitable cells andmost non-excitable cells and are identified using methods describedherein.

In one embodiment, it is desirable to utilize a cell that containscomponents of signaling and messenger systems that effects release ofcalcium from intracellular stores. For example, cells containingcomponents of receptor-mediated phospholipase C(PLC) activation systemsare used for physiological activation (via generation of IP₃) of storedepletion to facilitate monitoring of store-operated calcium entry.Receptor-mediated PLC activation occurs through distinct couplingmechanisms: PLC-β activation by G protein-coupled receptors (GPCRs) andPLC-γ activation by tyrosine kinase receptors and nonreceptor tyrosinekinases. Thus, cells containing a receptor-mediated PLC-activationsystem are monitored or assessed for store-operated calcium entry uponagonist activation of one or more receptors known to participate in thesystem.

In another embodiment, an assessment of intracellular calcium aftertreatment with a compound of Formula (I)-(XV) and Group A is made undera variety of conditions. Conditions are selected to evaluate the effectof test agent on a specific aspect of intracellular calcium. Forexample, reagents and conditions are known, and are used, forspecifically evaluating store-operated calcium entry, resting cytosoliccalcium levels, calcium buffering, and calcium levels of and calciumuptake by or release from intracellular organelles. in furtherembodiments, resting cytosolic calcium levels, intracellular organellecalcium levels and cation movement are assessed using any of the methodsdescribed herein. Such methods of assessing modulation in intracellularcalcium include, but are not limited to, calcium-sensitiveindicator-based measurements, such as fluo-3, mag-fura 2 and ER-targetedaequorin, labeled calcium (such as ⁴⁵Ca²⁺)-based measurements, andelectrophysiological measurements. Particular aspects of ion flux thatare assessed include, but are not limited to, a reduction (includingelimination) in the amount of ion flux, altered biophysical propertiesof the ion current, and altered sensitivities of the flux to activatorsor inhibitors of calcium flux processes, such as, for example,store-operated calcium entry. Reagents and conditions for use inspecifically evaluating receptor-mediated calcium movement and secondmessenger-operated calcium movement are also available.

Evaluation of Store-Operated Calcium Entry

In one aspect, compounds of Formula (I)-(XV) and Group A are added tocells under conditions that permit store-operated calcium entry to occurin order to assess the effects of compounds of Formula (I)-(XV) andGroup A on store-operated calcium entry.

For example, in one method cells are treated to reduce the calciumlevels of intracellular calcium stores and then analyzed for evidence ofion (e.g., calcium) influx in response thereto in the presence of acompound of Formula (I). Techniques for reducing calcium levels ofintracellular stores and for analyzing cells for evidence of ion (e.g.,calcium) influx are described herein.

In other methods, electrophysiological analysis of currents across acell-detached plasma membrane patch or an outside-out membrane vesicleare used to detect or monitor store-operated channel currents (e.g.,I_(SOC), I_(CRAC)) in the presence of a compound of Formula (I)-(XV) andGroup A.

Evaluation of Calcium Entry-Mediated Events

A number of molecules involved in calcium-regulated pathways are known.Evaluation of molecules involved in calcium-entry mediated events areused to monitor intracellular calcium, and are used, for example inscreening assays described herein to monitor the effects of compounds ofFormula (I)-(XV) and Group A. Examples of assays include but are notlimited to assays which detect, or determine the presence, levels,alteration of levels, production, modification (such as phosphorylationand dephosphorylation), translocation, degradation and activity ofmolecules involved in calcium-entry mediated events (see for example,Trevillyan et al. (2001) J. Biol. Chem. 276:48118-26). In someembodiments, the assays described herein are used with cells that havebeen treated with or contacted with a compound of Formula (I)-(XV) andGroup A, or that express an altered amount of a test molecule (such as aprotein involved in calcium regulation, including a STIM protein, Oraiprotein), or with control cells. In other embodiments, the assays arealso conducted in cells that have been stimulated with a physiologicalor non-physiological activator, or in unstimulated cells. The followingare representative assays for molecules involved in calcium-entrymediated events and are meant to be exemplary only. Other assays forthese molecules and assays for other molecules involved in calcium-entrymediated events are also employed in any of the screening and/ormodulation methods described herein.

β-Hexosaminidase Release

In mast cells, Ca²⁺ influx results in degranulation and release ofinflammatory mediators such as heparin, histamine and enzymes such asβ-hexosaminidase. In further embodiments, detecting and/or measuringrelease of such molecules is used to monitor intracellular calcium. Forexample, in other embodiments, media from mast cells are collected. Infurther embodiments, suitable substrate for β-hexosaminidase (e.g.p-nitrophenyl-acetyl-glucosamide) is then added and the absorbance ofthe resulting mixture assessed to measure the relative amount ofβ-hexosaminidase activity in the samples.

Calcium/Calmodulin-Dependent CaN Phosphatase Activity

The phosphatase calcineurin (CaN) dephosphorylates various proteins,affecting their activity and localization. In other embodiments, CaNactivity is assessed by incubating purified CaN and a CaN substrate, forexample a radiolabeled peptide corresponding to a sequence in the RIIsubunit of cAMP-dependent kinase, either with or without a compound ofFormula (I)-(XV) and Group A (see, Trevillyan et al. (2001) J. Biol.Chem. 276:48118-26). In further embodiments, the level of radiolabeledpeptide and/or the amount of free inorganic phosphate released ismeasured to assess CaN dephosphorylation activity.

NFAT Transcriptional Activity

The NFAT (nuclear factor of activated T cells) transcription factorregulates a number of genes in response to intracellular calcium levels.For example, NFAT proteins regulate the transcription of cytokine genesinvolved in the immune response. In other embodiments, promoters fromNFAT-regulated genes, and/or regulatory regions and elements from thesegenes, are used to monitor NFAT regulated expression and thereby monitorintracellular calcium. In further embodiments, reporter gene fusions areconstructed with NFAT regulated promoters or NFAT-regulated elementsoperably linked to a reporter gene such as luciferase, β-galactosidase,green fluorescent protein (GFP) or any other known reporter (see forexample, Published U.S. Application no. 2002-0034728). The amount ofreporter protein or activity is a measure of NFAT activity.

NFAT Phosphorylation

NFAT activation is regulated primarily through its phosphorylation,which in turn regulates its subcellular localization. In unstimulatedcells, NFAT is a hyperphosphorylated cytosolic protein. An elevation inintracellular Ca²⁺, induced by a variety of mechanisms, increases theactivity of the Ca²⁺-calmodulin-dependent phosphatase, calcineurin.Activated calcineurin dephosphorylates multiple serine residues withinthe regulatory region of the NFAT molecule. NFAT is rephosphorylated inresponse to decreases in Ca²⁺ levels or CaN inhibition.

The phosphorylation state of NFAT is monitored for example, byexpressing a detectably tagged NFAT protein in cells, such as a His6tagged-NFAT. Tagged NFAT is purified from cells using Ni²⁺chromatography and subjected to gel electrophoresis and staining orwestern blotting. More highly phosphorylated forms of NFAT aredistinguished by their slower migration. In further embodiments, thestate of phosphorylated NFAT is used as a measure of NFAT activation(see, Trevillyan et al. (2001) J. Biol. Chem. 276:48118-26).

NFAT Nuclear Localization

NFAT localization between the cytoplasm and nucleus is regulated by thephosphorylation state of NFAT. Phosphorylation of NFAT prevents nuclearlocalization by masking the nuclear localization sequence. NFAT nuclearlocalization are monitored, for example, by expressing fluorescentlytagged NFAT, for example, GFP-NFAT, in cells. In further embodiments,confocal microscopy is used to monitor nuclear localization of thetagged NFAT (see, Trevillyan et al. (2001) J. Biol. Chem. 276:48118-26).

Cytokine Secretion

In some embodiments, cytokine secretion, such as IL-2 secretion, ismonitored using protein detection assays. For example, supernatant iscollected from immune cells. In other embodiments, an ELISA assay orother suitable format with IL-2 antibodies is used to detect and/ormeasure the amount of IL-2 secreted as compared to control cells.Secretion of other cytokines, for example, TNF-α, is also detected insimilar assays.

Cytokine Expression

Expression of cytokines, such as, but not limited to IL-2, are assessedeither directly or indirectly in cells. For example, in indirectmethods, an IL-2 promoter are operably linked to a reporter gene such asluciferase or β-galactosidase, and the reporter construct introducedinto cells. In further embodiments, reporter gene expression ismonitored and compared to gene expression in control cells (see,Trevillyan et al. (2001) J. Biol. Chem. 276:48118-26). In otherembodiments, expression of endogenous or recombinant IL-2 mRNA orprotein is assessed.

T Cell Proliferation

Cytokines such as IL-2 are necessary for T-cell proliferation inresponse to mitogen or alloantigen stimulation, and thus T-cellproliferation is altered by changes in cytokine expression or secretion.In some embodiments, T cells are induced, such as with concanavalin A oralloreactive lymphocytes and T cell proliferation measured, for example,by subjecting cells to a pulse of ³H-thymidine and measuring³H-thymidine incorporation (see, Trevillyan et al. (2001) J. Biol. Chem.276:48118-26).

In further embodiments, the modulation (e.g. inhibition or reduction) ofSOCE by compounds of Formula (I) is determined by evaluation of any ofthe following criteria:

a. there is direct inhibition of increased [Ca²⁺]i as measured by acalcium indicator;

b. there is a direct inhibition of I_(SOC) or I_(CRAC) as measured bypatch clamp;

c. there is inhibition of downstream signaling functions such ascalcineurin activity, NFAT subcellular localization, NFATphosphorylation, and/or cytokine, e.g., IL-2, production; or

d. there are modifications in activation-induced cell proliferation,differentiation and/or apoptotic signaling pathways.

Animal Models

Animal models that are used in embodiments of the methods furtherinclude animals, such as, but not limited to non-human animals, whichhave, in at least some of their cells, an alteration or defect in, oraberrant functioning of, a cellular process which relies on or isregulated by intracellular calcium. Cellular processes that rely on orare regulated by intracellular calcium include, for example, cellularactivation, gene expression, cellular trafficking, and apoptosis. Insome embodiments, are diseases/disorders that involve defects that areat least partially compensated for by modulation of intracellularcalcium include, but are not limited to: autoimmune disorders, includingrheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome(cytokines associated with lymphocyte invasion of salivary epithelialcells can reduce calcium mobilization in parotid cells; also, T-cellactivation, including activation of transcription factors, cytokine geneexpression and cell proliferation, depends on sustained elevation ofintracellular calcium level provided by store-operated calcium influx),asthma (store-operated calcium entry also plays an important role inmediating bronchial constriction and bronchial smooth muscle cellproliferation), glomerulonephritis and glomerular inflammation (changesin intracellular calcium, such as by store-operated calcium entry,signal monocyte adhesion in a co-culture model of glomerularinflammation).

Types of animal models include, but are not limited to, non-humananimals, such as non-human invertebrates and vertebrates and non-humanmammals, rodents (e.g., mice, rat and hamster), cows, chickens, pigs,goats, dogs, sheep, insects, Drosophila, nematodes, worms, C. elegans,monkeys, gorillas, and other primates.

Animal models include transgenic and non-transgenic animals. One exampleof such an animal model that are used in particular embodiments of themethods is a rodent model of airway hyperresponsiveness (AHR), acharacteristic of asthma. This model are generated, for example, bysensitization through immunization with ovalbumin followed by exposureto aerosolized ovalbumin and challenge by cholinergic stimulation (e.g.,via administration of methacholine or acetylcholine) (see, e.g., Xu etal. (2002) J. Appl. Physiol. 93:1833-1840; Humbles et al (2002) Proc.Natl. Acad. Sci. 99:1479-1484). Airway hyperresponsiveness (which insome embodiments are evaluated using methods such as, for e.g., usingbarometric plethysmography to record respiratory pressure curves andthrough measurement of pulmonary parameters such as pulmonaryconductance and pulmonary compliance) are assessed and compared inanimals treated and not treated with a compound of Formula (I)-(XV) andGroup A. A further example of an animal model that is used inembodiments of the methods is a rodent model of mesangial proliferativeglomerulonephritis, which is generated, for example, by administrationof anti-Thy1.1 antibody (see, e.g., Jefferson and Johnson (1999) J.Nephrol. 12:297-307). Any number of parameters indicative ofglomerulonephritis or renal dysfunction (e.g., mesangial cellproliferation, blood pressure, urinary protein excretion, creatinineclearance, glomerulosclerosis index and other parameters) are in someembodiments, evaluated and compared in animals treated with and nottreated with test agent. The non-obese diabetic (NOD) mouse, an inbredmouse strain that spontaneously develops an autoimmune diabetes thatshares many immunogenetic features with Type 1 diabetes mellitus, isanother example of an animal model that is used in one embodiment of themethods. These mice also manifest many characteristics of autoimmuneexocrinopathy (such as Sjorgen's syndrome) including declining exocrinetissue secretory function (see, e.g., Humphreys-Beher and Peck (1999)Arch. Oral Biol. 44 Suppl 1:S21-25 and Brayer et al. (2000) J Rheumatol.27:1896-1904). Characteristics relevant to Sjorgen's syndrome (e.g.,lymphocytic infiltrates in exocrine glands (e.g., salivary and lacrimalglands), presence of dendritic cells and macrophages in submandibularglands, integrity of the lacrimal gland by measurement of basal andstimulated tear secretion, saliva flow rates and amylase activity) areevaluated and compared in animals treated with and not treated with acompound of Formula (I)-(XV) and Group A. In further embodiments, ananimal (e.g., rodent) model of autoimmune disease is also used inparticular embodiments of the methods. Such animals include rat modelsavailable through the National Institutes of Health (NIH) Autoimmune RatModel Repository and Development Center (Bethesda, Md.; accessible atwww.ors.od.nih.gov/dirs/vrp/ratcenter). One rat model of rheumatoidarthritis (RA) and related chronic/inflammatory autoimmune diseases isthe collagen-induced arthritis (CIA) model (see, e.g., Griffiths andRemmers (2001) Immunol. Rev. 184:172-183). Characteristic phenotypes ofautoimmune disease (e.g. altered levels of immune reactivity toself-antigens, chronic inflammation of autoantigen-expressing targetorgans, and activation and participation of invading mononuclear cellsand tissue fibroblasts in organ damage) are in some embodiments,evaluated and compared in animals treated with and not treated with acompound of Formula (I)-(XV) and Group A. In other embodiments, ananimal (e.g., rodent) model of neuropathic or inflammatory pain is alsoused in one embodiment of the methods. For example, one rat model ofneuropathic pain involves development of tactile allodynia (exaggeratedresponse to otherwise innocuous stimuli) after ligation of lumbar spinalnerves (see, e.g., Chaplan et al. (1994) J. Neurosci. Methods 53:55-63and Luo et al. (2001) J. Neurosci. 21:1868-1875). Tactile allodynia, onecharacteristic feature of neuropathic pain, are evaluated (e.g., byevaluating paw withdrawal threshold in response to application ofpressure) and compared in animals treated and not treated with acompound of Formula (I)-(XV) and Group A.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein. The starting materialsand reagents used for the synthesis of the compounds described hereinare synthesized or are obtained from commercial sources, such as, butnot limited to, Sigma-Aldrich, Acros Organics, Fluka, and FischerScientific.

Biological Examples

In Vitro Examples

Example 1 In Vitro Screening for Agents that Modulate IntracellularCalcium Levels

Fluorescence-based assays are used for screening the compounds describedherein, such as compounds of Formula (I)-(XV) or Group A which modulateintracellular calcium.

A. Fluorescence-based Assay of Store-Operated Calcium Entry inOrai1/STIM1 Stable Cells.

Cells:

Cells stably expressing recombinant human STIM1 and Orai1 were generatedby transfecting a human Orai1 expression plasmid (pcDNA3.1-Orai1-cmyc)into HEK-293 cells stably overexpressing human STIM1 (Roos et al. 2005JCB 169(3): 435-445). Colonies of cells stably expressing both STIM1 andOrai1 proteins were selected and then subcloned by limiting dilution.Cells were cultured at 37° C./6% CO₂ in complete medium with 10% FBS andappropriate selection markers.

Assay

The day prior to performing the assay Orai1/STIM1 stable cells areplated in 50 μL of complete medium at 90-95% confluence in a 384 wellplate. Cells are grown at 37° C./6% CO₂ overnight. On the day of theassay, 1.5 μM fluo-4-AM (Invitrogen) in complete medium is added to thecells, which are then incubated for 1 hour at RT. Cells are washed oncein Ca²⁺-free HBSS (Hank's buffered saline solution) and 35 μl ofCa²⁺-free HBSS is added to each well. Test compounds are added to wellsin a 10 μL Ca²⁺-free HBSS solution, prepared at 4.5× the desired finalconcentration, and incubated for 30 minutes at RT. The initial baselinefluorescence signal is then measured with a FLIPR³⁸⁴ (Molecular Devices)plate reader. Calcium entry is initiated by adding 5 μl of 10×CaCl₂ (10mM) in HBSS, and changes in cellular fluorescence are measured with theFLIPR³⁸⁴ plate reader. In each well, the magnitude of the fluorescencesignal as a result of calcium entry into the cell is determined bycalculating the difference between the peak fluorescence signal measuredafter calcium addition and the initial baseline fluorescence signal(designated Peak-Basal). IC₅₀ values are typically calculated as theconcentration that inhibited 50% of the Peak-Basal signal.

Compounds of Formula (I)-(XV) or Group A are expected to be inhibitoryin this assay.

B. Fluorescence-Based Assay of Store-Operated Calcium Entry inRBL-2H₃Cells.

Cells:

RBL-2H3 cells are obtained from ATCC and maintained in complete mediumwith 10% FBS at 37° C./6% CO₂.

Assay:

The day prior to performing the assay, RBL-2H3 cells are plated in 50 μLof complete medium in a 384 well plate. Cells are grown at 37° C./6% CO₂overnight and grow to 50-60% confluence by the next day. On the assayday, 1.5 μM Fluo-4-AM dye (Invitrogen) in complete medium is added andincubated for 1 hour at RT. Cells are washed twice in Ca²⁺-free HBSSbuffer and 35 μL Ca²⁺-free HBSS buffer is added to each well. 10 μL of atest compound prepared in a Ca²⁺-free HBSS solution at 4.5× of thedesired concentration is added to a well and incubated for 5 minutes atRT. 10 μL of thapsigargin prepared in a Ca²⁺-free HBSS solution at 5.5×of the desired concentration (5.5 uM) is added to each well andincubated for an additional 25 minutes. The initial baselinefluorescence signal is measured with a FLIPR³⁸⁴ (Molecular Devices)plate reader. 5 μL of 12× calcium in HBSS (12 mM) is added and changesin cellular fluorescence are measured with the FLIPR³⁸⁴ plate reader. Ineach well, the change in the fluorescent signal as a function of timedue to calcium entry into the cell is determined by calculating thedifference between the fluorescent signal measured 7 seconds aftercalcium addition and the initial baseline fluorescence signal at timezero (t=0). This parameter is designated Upslope. The IC₅₀ value iscalculated as the concentration at which 50% of the Upslope isinhibited.

Compounds of Formula (I)-(XV) or Group A are expected to be inhibitoryin this assay.

C. Fluorescence-Based Assay of Store-Operated Calcium Entry in JurkatCells.

Cells:

Jurkat E6-1 cells were obtained from ATCC and maintained in completemedium with 10% FBS at 37° C./6% CO₂.

Assay:

The day prior to performing the assay, Jurkat E6-1 cells are seeded at adensity of 2 million cells/mL in complete medium in a T-175 flask. Cellsare grown at 37° C./6% CO₂ overnight. On the following day, 1.5 μMFluo-4-AM dye (Invitrogen) in complete medium is added and incubated for1 hour at RT. Cells are harvested, washed twice in Ca²⁺-free HBSS bufferand plated in 35 μL Ca²⁺-free HBSS buffer in a 384 well plate. 10 μL ofa test compound prepared in a Ca²⁺-free HBSS solution at 4.5× of thedesired concentration is added to a well and incubated for 5 minutes atRT. 10 μL of thapsigargin prepared in a Ca²⁺-free HBSS solution at 5.5×of the desired concentration (5.5 uM) is added to each well andincubated for an additional 25 minutes. The initial baselinefluorescence signal is measured with a FLIPR³⁸⁴ (Molecular Devices)plate reader. 5 μL of 12× calcium in HBSS (12 mM) is added and changesin cellular fluorescence are measured with the FLIPR³⁸⁴ plate reader. Ineach well, the change in the fluorescent signal as a function of timedue to calcium entry into the cell is determined by calculating thedifference between the fluorescent signal measured 7 seconds aftercalcium addition and the initial baseline fluorescence signal at timezero (t=0). This parameter is designated Upslope. The IC₅₀ value iscalculated as the concentration at which 50% of the Upslope isinhibited.

Example 2 In Vitro I_(CRAC) Patch Clamp Assay

Objective

The objective of this assay is to examine the in vitro effects of testcompounds on cloned CRAC channels (Orai1 and STIM1 genes stablyexpressed in HEK293 cells), responsible for I_(CRAC), the calciumrelease activated calcium channel current.

Test and Control Articles

Formulation: Test article stock solutions are prepared in dimethylsulfoxide (DMSO) and stored frozen. Test article concentrations areprepared fresh daily by diluting stock solutions into an appropriateexternal recording buffer. If necessary, test article formulations aresonicated (Model 2510, Branson Ultrasonics, Danbury, Conn.), at ambientroom temperature to facilitate dissolution. In certain instances, thetest solutions contain up to 0.1% DMSO and the presence of 0.1% DMSOdoes not affect channel current.

Test Article Concentrations and Quantity

Typically, the effects of three (3) concentrations of each test articleare evaluated (0.1, 1, and 10 μM). Test articles are weighed andprepared as 30 mM or 10 mM stock solutions in DMSO. The DMSO stock isdiluted in external recording buffer to prepare a 10 μM test solution(final DMSO 0.03% or 0.1%). The 10 μM test solution is diluted inexternal recording buffer to prepare 1 μM and 0.1 μM test solutions.Test solutions contain up to 0.1% DMSO at the highest concentrationwhich are diluted in test solutions at lower concentrations.

Positive Control Article

Stock solutions of the positive control article are prepared in batches,aliquoted for individual use, stored frozen and used within six months.The positive control concentration is prepared fresh daily by dilutingstock solutions into external recording buffer. The final DMSOconcentration in the test positive control article is up to 0.1% of thesolution.

Negative Control Article

The negative control article is 0.1% DMSO in external recording buffer.

Cloned Ion Channel Test Systems

Cells are maintained in tissue culture incubators per CalciMedicastandard protocols. Stocks are maintained in cryogenic storage. Cellsused for electrophysiology are plated in plastic tissue culture dishes.

HEK293 Cells

HEK293 cells are stably transfected with the appropriate ion channelcDNAs (Orai1/STIM1). Cells are cultured in DMEM (Gibco 11960)supplemented with 10% fetal bovine serum (Gibco 10082), 100 U/mLpenicillin G sodium, 1 mM Na pyruvate (Gibco 11360), 100 μg/mLstreptomycin sulfate (Gibco 10378), 0.5 mg/ml geneticin (Gibco10131-035) and 50 μg/ml zeocin (Invitrogen 45-0430). Cells should bemaintained at ≦80% confluence. The day before testing, cells in culturedishes are washed once with calcium/magnesium-free D-PBS, treated withtrypsin/EDTA and re-suspended in the culture media and counted. Cellsare then diluted in culture medium with 1% fetal bovine serum and platedat low density (5-10K) onto poly-D-lysine coated glass coverslips in24-well tissue culture dishes and placed in a tissue culture incubatorset at 37° C. in a humidified 95% air, 6% CO₂ atmosphere.

Test Methods

Recording Chamber and Perfusion of Test Articles

Glass coverslips containing cells are transferred to a recording chamber(Warner Instruments) with continuous perfusion of external recordingbuffer. During recordings of I_(CRAC), all treatments are delivered bygravity-fed bath perfusion from disposable syringe reservoirs viadisposable polyethylene tubing feeding into a Teflon manifold. The flowrate is set between 1.2-1.5 ml/min assuring complete solution exchangein ±1 min. All experiments are performed at ambient temperature.

Test Article Treatment Groups

For experiments where the test article is applied for 10 minutes thetreatment paradigm is summarized in Table 1. Control recording buffer isperfused for five (5) minutes while I_(CRAC) develops and a stablebaseline is established; each cell is used as its own control. Each testarticle is applied to naïve cells (n≧2, where n=the numbercells/concentration; at 1 concentration/cell) for a duration of ten (10)minutes (Table 1). The test article is washed off for ten (10) minutesto look for reversibility of the effect. External recording saline withno calcium is perfused for two (2) minutes to determine the backgroundcurrent in the absence of I_(CRAC). Control saline containing calcium isreapplied for three (3) minutes.

For experiments where the test article is applied for 30 minutes priorto recording of I_(CRAC), the treatment paradigm is summarized in Table2. Prior to the start of each experiment, cells are incubated withcompound for 30 minutes at room temperature, and compound remainspresent throughout I_(CRAC) recordings. Control cells are exposed tovehicle only. After break-in and establishment of the whole-cell patchclamp configuration, recording buffer±compound is perfused for ten (10)minutes. At the end of the 10 min period the amplitude of I_(CRAC) ismeasured. The effects of compounds are determined by comparing theI_(CRAC) signal in cells pretreated with compound to the signal in cellspretreated with vehicle.

TABLE 1 Test Article Schedule for 10-minute Application Studies EpochSolution Exposure time 1 Baseline control/ 5 minutes stabilization 2Test article 10 minutes  3 Wash 10 minutes  4 0 calcium 2 minutes 5control 3 minutes

TABLE 2 Test Article Schedule for 40-minute Application Studies EpochSolution Exposure time Test article 30 minutes 1 Test article 10 minutes2 Wash 10 minutes 3 0 calcium  2 minutes 4 control  3 minutesControl Treatment Groups

As a negative control, 0.1% DMSO is applied to naïve cells (n 2, wheren=the number cells. This is used to monitor the magnitude of rundown ofI_(CRAC). As a positive control, 1 μM of4-(4-bromophenyl)-2-(3-fluorobenzamido)thiophene-3-carboxylic acid isroutinely applied to naïve cells (n 2, where n=the number cells).

Whole Cell Patch Clamp Procedures

Standard whole cell patch clamp procedures are used. The compositions ofthe extracellular and intracellular solutions are shown in Tables 3 and4. Cells are visualized on an inverted microscope (Olympus IX71) andvoltage clamped using a Multiclamp 700B amplifier and PClamp software(Axon Instruments). Briefly, borosilicate patch pipettes filled withintracellular solution (Appendix 1) are positioned onto the cellmembrane. Once a GΩ seal is formed, suction is applied until the patchruptures and the whole cell configuration is established. The quality ofthe configuration will be evaluated with the “membrane test” in Clampexto determine cell capacitance (Cm), input resistance (Rm), accessresistance (Ra), and holding current at −50 mV (Ih). Data are stored onthe CalciMedica computer network (and backed-up nightly) for off-lineanalysis.

TABLE 3 Extracellular Solution Composition (concentration in mM) NaCl120 TEA-Cl  10 HEPES  10 CaCl₂  10 (and 0) MgCl₂  2 (and 12) glucose  10

The pH is adjusted to 7.2 with NaOH and the final osmolarity is adjustedto 325 with sucrose. Solutions are prepared daily. Chemicals used insolution preparation are purchased from Sigma-Aldrich (St. Louis, Mo.),unless otherwise noted, and are of ACS reagent grade purity or higher.

TABLE 4 Intracellular Solution Composition (concentration in mM)Cs-glutamate 120 HEPES 10 BAPTA 20 MgCl₂ 3

The pH is adjusted to 7.2 with CsOH. Solutions are prepared in batches,aliquoted, and refrigerated until use. A fresh aliquot is used each dayand stored on ice throughout the day. Chemicals used in solutionpreparation are purchased from Sigma-Aldrich (St. Louis, Mo.), unlessotherwise noted, and are of ACS reagent grade.

I_(CRAC) Test Procedures

I_(CRAC) from the Orai1/STIM1 channel complex is activated by passivedepletion of intracellular calcium stores using 20 mM BAPTA in theintracellular solution. Voltage clamp data is acquired using Clampexsoftware to elicit a stimulus voltage protocol (shown in Table 5)applied every six (6) seconds. Currents are digitized at 10 kHz andfiltered at 2 kHz. Whole cell capacitive compensation is employed.Representative I_(CRAC) traces are shown in FIG. 2.

TABLE 5 Voltage Clamp Protocol Voltage Description Vh +30 mV to minimizecalcium entry in-between sweeps Vstep to 0 mV for 10 ms to evaluate“zero” current Vstep to −100 mV for 10 ms to measure I_(CRAC) at highdriving force Vramp to +100 mV over 50 ms to monitor inwardly rectifyingprofile of I_(CRAC) Vstep to +50 mV for 10 ms to estimate leak currentData Analysis

Data analysis is performed using Clampfit software. I_(CRAC) is measuredat −100 mV and the current measured after 5 min is used as the baselinecontrol. For 10-minute application studies, the current measured after10 min application of the test article is normalized to the baselinecurrent and expressed as % control. For 40-min application studies, thecurrent measured at the end of 10 minutes of I_(CRAC) recording time isused as the comparator. The current measured in “0 calcium” buffer isused to subtract background leak current. Data points for each testarticle concentration (n≧2) are fitted to a sigmoid function (SigmaPlot)to determine the IC₅₀ and Hill slope.

In Vivo Examples

Example 3 In Vitro Assay of Mast Cell Degranulation

Cells:

RBL-2H3 cells were obtained from ATCC and maintained in complete mediumwith 10% FBS at 37° C./6% CO₂.

Assay:

a) Stimulation with 1 μM thapsigargin/20 nM TPA

The day prior to performing the assay, RBL-2H3 cells are plated in a 96well plate. Cells are grown at 37° C./6% CO₂ overnight. On the followingday, cells are washed twice in HBSS Buffer with 1.8 mM CaCl₂ and 1.75%fetal bovine serum (FBS). 70 μL of a test compound prepared in HBSSBuffer with 1.8 mM CaCl₂+1.75% FBS is added and incubated for 10 minutesat 37° C./6% CO₂. Cells are stimulated by the addition of 7 μL of 11×thapsigargin/TPA (11 μM thapsigargin/220 nM TPA) and incubated at 37°C./6% CO₂ for 120 minutes. Media is collected and cell lysates areprepared by the addition of 70 μL of 0.05% Triton X-100 in HBSS with 1.8mM CaCl₂. Levels of β-hexosaminidase are measured in both the media andthe cell lysates. The 13-hexosaminidase assay is performed by adding 40μL of 1 mM p-nitrophenyl-acetyl-glucosamide substrate in 0.05M sodiumcitrate (pH 4.5) to 10 μL of sample (conditioned medium or cell lysate),incubating 60 minutes at 37° C., then adding 100 μL 0.05M sodiumcarbonate/0.05M sodium bicarbonate (pH 10.5), mixing thoroughly andreading the absorbance at 405 nm. The percentage of β-hexosaminidasereleased is calculated as follows: A405 (media)/[A405 (media)+A405(lysate)]. The IC₅₀ value is calculated as the concentration at which50% of the β-hexosaminidase released in vehicle treated cells isinhibited.

Compounds of Formula (I)-(XV) or Group A are expected to be inhibitoryin this assay.

b) Stimulation with IgE-DNP

The day prior to performing the assay, RBL-2H3 cells are plated in 200μL of complete medium in a 96 well plate for 1 hour. 20 μL of 11×DNP-IgE are added and cells are grown at 37° C./6% CO₂ overnight. On thefollowing day, cells are washed twice in HBSS Buffer with 1.8 mM CaCl₂and 1.75% fetal bovine serum (FBS). 70 μL of a test compound prepared inHBSS Buffer with 1.8 mM CaCl₂ and 1.75% is added and incubated for 10minutes at 37° C./6% CO₂. Cells are stimulated by the addition of 7 μLof 11×DNP-BSA and incubated at 37° C./6% CO₂ for 30 minutes. Media iscollected and cell lysates are prepared by the addition of 70 μl of0.05% Triton X-100 in HBSS with 1.8 mM CaCl₂. Levels of β-hexosaminidaseare measured in both the media and the cell lysates. Theβ-hexosaminidase assay is performed by adding 40 μL of 1 mMp-nitrophenyl-acetyl-glucosamide substrate in 0.05M sodium citrate (pH4.5) to 10 μL of sample (conditioned medium or cell lysate), incubating60 minutes at 37° C., then adding 100 μL 0.05M sodium carbonate/0.05Msodium bicarbonate (pH 10.5), mixing thoroughly and reading theabsorbance at 405 nm. The percentage of β-hexosaminidase released iscalculated as follows: A405 (media)/[A405 (media)+A405 (lysate)]. TheIC₅₀ value is calculated as the concentration at which 50% of theβ-hexosaminidase released in vehicle treated cells is inhibited.

Example 4 In Vitro Assay of Cytokine Release from T Cells

Cells:

Jurkat E6-1 cells are obtained from ATCC and maintained in completemedium with 10% FBS at 37° C./6% CO₂.

Assay:

The day prior to performing the assay, Jurkat T cells are plated in 90μL of HBSS Buffer with 1.8 mM CaCl₂ and 1.75% fetal bovine serum (FBS)in a 96 well plate at a density of 1.5×105 cells/well for 3 hours. 10 μLof 10× test compound prepared in HBSS is added and incubated for 10minutes at 37° C./6% CO₂. Cells are stimulated by the addition of 10 μLof 11×PHA/TPA (27.5 μg/mL PHA/880 nM TPA) and incubated at 37° C./6% CO₂for 20 hours. On the following day, the supernatants are collected andassayed for IL-2 levels by ELISA according to the manufacturer'sprotocols. The IC₅₀ value is calculated as the concentration at which50% of secreted IL-2 in vehicle treated cells is inhibited.

Compounds of Formula (I)-(XV) or Group A are expected to be inhibitoryin this assay.

Example 5 Dose-Response Effects of a compound of Formula (I)-(XV) orGroup A, CSA or Rapamycin in Mouse Footpad DTH

Purpose: Determine dose-response effects of Test Compound on mBSAinduced DTH response in foot pads when dosing is done during thesensitization as well as induction phase.

Animals: Male Swiss Webster Mice approx. 20-25 grams at start of study.

Materials: Methylated BSA (Sigma) Freund's complete adjuvant (Difco)plus supplemental M. tuberculosis H37 RA (Difco).

General Study Design:

Mice are anesthetized with Isoflurane and given intradermal antigeninjections of 0.1 ml at the base of the tail (D0, D07). Antigen isprepared by making a 4 mg/ml solution in sterile water. Equal volumes ofantigen and Freund's complete adjuvant to which 4 mg/ml MTB are added(sonicate for 5 minutes after adding MTB to oil), are emulsified by handmixing until a bead of this material holds its form when placed inwater. Treatment with test compound is initiated on day 0, qd (24 hrintervals) and continued through day 10 when challenge is done.

On day 10 animals are injected into the right hind footpad with 20 μl of10 mg/ml mBSA. Five unsensitized males are injected with mBSA into thefootpad. Twenty-four hours later (day 11) the right and left hind pawsare transected at the medial and lateral malleolus and weighed and theweight difference induced by injection of antigen is determined.

Statistical Analysis. Paw weights (mean±SE) for each group are analyzedfor differences using a Student's t test or ANOVA with Dunnett's posttest. Statistical significance is set at p≦0.05.

TABLE 5 Treatment Groups Males Group N Treatment 10 ml/kg qd, po 1 5Normal controls (no sensitization) Inject mBSA into right only 2 8DTH+Vehicle (70% PEG400/30% Water) 3 8 DTH+ Test Compound (50 mg/kg, po,qd) 4 8 DTH+ Test Compound (100 mg/kg, po, qd) 5 8 DTH+ Test Compound(200 mg/kg, po, qd) 6 8 DTH+ Test Compound (300 mg/kg, po, qd) 7 8 DTH+CSA (100 mg/kg qd, ip) 8 8 DTH+Rapamycin (5 mg/kg qd, ip)

Compounds of Formula (I)-(XV) or Group A are expected to be inhibitoryin this model.

Example 5A Pharmacokinetic Data of a Compound of Formula (I)-(XV) orGroup A in Rats

The bioavailability and plasma pharmacokinetic properties in rats ofCompound of Formula (I)-(XV) or Group A administered orally in 25%PEG400/20% ethanol/55% H₂O vehicle. Two treatment groups, 1) an i.v.dose group at 2 mg/kg; and 2) an oral dose group at 10 mg/kg areadministered to Male Sprague-Dawley rats (3 rats per group), weighingapproximately 250-300 gm. Up to 10 time points are collected for eachgroup. Typical time points are: predose, 15, 30 minutes, 1, 2, 4, 6, 8,12 and 24 hrs. Up to 300 μL of whole blood are collected via jugularvein cannula at each time point. Whole blood is collected intoanticoagulant containing microcentrifuge tubes and centrifuged at 5000rpm in a microcentrifuge for 5 minutes before plasma is transferred to aclean microcentrifuge tube. The plasma samples undergo bioanalyticalanalysis.

Example 6 Effect of Test Compound in Rat Collagen Induced Arthritis(CIA) Model

Purpose: Determine efficacy of Test Compound administered by oral dosingqd, in inhibiting the inflammation, cartilage destruction and boneresorption of developing type II collagen arthritis in rats.

Animals: Female Lewis rats (Charles River#7246950), weighing 125-150 gat the start of the study. 40 rats are injected with collagen to getsolid responders on days 10 and 11. Four nonimmunized animals serve asnormal controls.

Materials: Test Compound, Type II collagen, Freund's incompleteadjuvant, acetic acid. Test Compound is prepared at a concentration of10 mg/ml in 50% PEG400/50% water. Collagen is prepared by making a 4mg/ml solution in 0.01N Acetic acid. Equal volumes of collagen andFreund's incomplete adjuvant, are emulsified by hand mixing until a beadof this material holds its form when placed in water.

General Study Design: Animals (10 rats/group for arthritis, 4 rats/groupfor normal control).

Animals in the arthritis groups are anesthetized with isoflurane andgiven collagen injections (D0); each animal gets 300 μl of the mixturespread over 3 subcutaneous sites on the back. On Day 6 (D6) the animalsare anesthetized again and given a second collagen injection, as before.

Oral dosing of Test Compound at 24 hour intervals (qd) is initiated onDay 0 using a dose volume of 5 ml/kg for oral solutions. Rats areweighed on Days 0, 3, 6, and 9-17 of arthritis, and caliper measurementsof ankles taken every day beginning on Day 9. Final body weights aretaken on Day 17 of arthritis. On Day 17, all animals are anesthetizedfor terminal blood draw and then euthanized. Subsequently, hind paws andknees are removed, the hind paws are weighed and then (with knees)placed in formalin for processing for microscopy. Livers, spleen andthymus and kidneys are also removed, trimmed of extraneous tissue andweighed. Kidneys are retained in formalin for histopathology.

Sampling will occur over 1 day and involves groups 2-5 with samplesretained from all groups. This results in all animals being treatedsimilarly and is important for clinical parameters and final liverweights.

Compounds of Formula (I)-(XV) or Group A are expected to produce asignificant reduction of arthritis in this model.

Example 7 Effect of compounds of Formula (I)-(XV) or Group A onDNBS-Induced Colitis in Rats

Procedure: Male Wistar rats weighing 200±20 g are fasted for 24 hoursprior to use. Distal colitis is induced by intra-colonic instillation ofDNBS (2,4-dinotrobenzene sulfonic acid, 20 mg in 0.5 ml ethanol 30%)with a catheter of 12 cm in length, followed by gentle injection of air(2 ml) through the catheter to ensure that the solution remain in thecolon. The animals are divided into groups of 5 each. Test substance andvehicle are administered either daily or twice daily by appropriateroute of administration 24 hour and 1 hour before DNBS instillation andthen for 6 consecutive days thereafter. One normal control group istreated with 0.9% NaCl alone without DNBS challenge. The animals aresacrificed 12 hours after the final bid dose and 24 hours after thefinal daily dose and the colon is removed and weighed. During theexperiment, body weight, fecal occult blood and stool consistency aremonitored daily. Furthermore, when the abdominal cavity is opened beforeremoval of the colon, adhesions between the colon and other organs arenoted as is the presence of colonic ulceration after removal andweighing of each colon (a macroscopic damage score is recorded accordingto established score criteria). The colon-to-body weight ratio iscalculated according to the formula: Colon (g)/BW×100. The “Net”increase in ratio of Vehicle-control+DNBS group relative toVehicle-control group is used as a base for comparison with individualtreated groups and expressed as “Dec. (%)” (percent decrease). A 30% ormore (≧30%) reduction in colon-to-body weight ratio, relative to thevehicle treated control group, is considered significant.

Sulfasalazine is used as the standard test agent. (Hogaboam C M, et al.,An orally active non-selective endothelin receptor antagonist, bosentan,markedly reduces injury in a rat model of colitis. Eur J Pharmacol. 309:261-269, 1996; Yue G, et al., In some embodiments, the 21-aminosteroidtirilazid mesylate ameliorates inflammatory bowel disease in rats. JPharmacol Exp Ther. 276: 265-270, 1996.)

Compounds of Formula (I)-(XV) or Group A are expected to reduce colitisin this model.

Example 8 Effect of Compounds of Formula (I)-(XV) or Group a onRejection of Skin Transplants in Rats

Procedure. Specific pathogen free Lewis and Brown Norway rats 10 weeksof age are purchased from Charles River and housed under cleanconventional conditions. The animals are handled and allowed toacclimatize for a period of two weeks. Skin donors: female Brown Norwayrats, 10 weeks of age. Skin recipients: female Lewis rats, 10 weeks ofage.

The donor Brown Norway rats are killed to serve as donors of 5 to 8 skintransplants. Directly after killing the Brown Norway rats, the abdominalskin of the rats is shaved and skin transplants of 20 mm in diameter insize are taken. After removal of connective tissue, these grafts aretransplanted onto Lewis rats. This is performed by shaving the upperdorsal skin of the Lewis rat under isoflurane anesthesia, removing apiece of skin of 15 mm in diameter by punching and replacement with askin transplant derived from the Brown Norway rat.

During the study each graft is fixated by 4-6 stitches using Safil 6/0violet (B Braun, Aesculap) and covered by Paraffin Gauze Dressing BP(3×3 cm, Smith & Nephew), a piece of gauze and surgical tape. Thisadaptation minimizes the chance of loosing a transplant for reasonsdifferent from rejection.

In all cases, transplants are protected with a bandage; these areremoved after six days to enable daily inspection of the transplant.

Rejection is monitored by evaluating first signs of inflammation(redness) and necrosis (hardening and blackening of the graft).

Phase II Clinical Trial of the Safety and Efficacy of Compounds ofFormula (I)-(XV) or Group A in Patients with Active RheumatoidArthritis.

The purpose of this phase II trial is to investigate the safety,tolerability, PK, PD, and efficacy of single and repeat intravenousinfusions of a compound of Formula (I)-(XV) or Group A in patients withactive rheumatoid arthritis.

Patients: Eligible subjects will be men and women between the ages of 18and 75

Criteria:

Inclusion Criteria:

-   -   All subjects must use acceptable contraception to ensure that no        pregnancies occur during the course of the study and for at        least 12 weeks after dosing for males and for 32 weeks after        dosing for females;    -   Body mass index within the range 18.5-35 kg/m² inclusive, in        addition to a weight range of 55-95 kg;    -   The subject must be capable of giving informed consent and can        comply with the study requirements and timetable;    -   The subject must have a diagnosis of RA according to the revised        1987 criteria of the American College of Rheumatology (ACR);    -   The subject must have a DAS28 disease activity score of greater        than 4.2 at screening and pre-dose;    -   The subject must have a CRP serum level of >/0.5 mg/dl or an ESR        level 28 mm/hour at screening and pre-dose;    -   The subject has NOT received any biological therapy in the past,        including biologicals for the treatment of rheumatoid arthritis;    -   The subject must have liver function tests including alanine        transaminase (ALT) and aspartate transaminase (AST) within 1.5        times the upper limit of normal (ULN) and alkaline phosphatase        (ALP) within 3 times ULN at screening. The patient must also        have total bilirubin within the ULN at screening;    -   The subject must have received at least 3 months of methotrexate        and must be on a stable dose of methotrexate (up to 25 mg/week)        for at least 8 weeks prior to screening and be willing to remain        on this dose throughout the study;    -   If sulfasalazine is being taken in addition to methotrexate, the        subject must be on a stable dose for at least 4 weeks prior to        screening and be willing to remain on this dose throughout the        study;    -   If hydroxychloroquine or chloroquine is being taken in addition        to methotrexate, the subject must be on a stable dose for at        least 3 months prior to screening and be willing to remain on        this dose throughout the study;    -   Those subjects on other oral anti-rheumatic therapies, which may        include Non Steroidal Anti Inflammatory Drugs (NSAIDs), COX-2        inhibitors, oral glucocorticoids e.g. prednisolone (˜10 mg/day)        must be on stable dosing regimens for at least 4 weeks prior to        screening and be willing to remain on this regime throughout the        study. Subjects receiving intramuscular glucocorticoids e.g        methylprednisolone (˜120 mg/month) must be on a stable dosing        regimen for at least 3 months prior to screening and be willing        to remain on this regimen throughout the study;    -   The subject must be on a stable dose of folate supplements (5        mg/week) for at least 4 weeks prior.        Exclusion Criteria:    -   Any clinically relevant abnormality identified on the screening        medical assessment, laboratory examination (e.g. haematology        parameter outside the normal limits), or ECG (12 Lead or        Holter);    -   The subject has a positive Hepatitis B surface antigen or        Hepatitis C antibody result at screening;    -   The subject has a history of elevated liver function tests on        more than one occasion (ALT, AST and ALP >3× Upper Limit of        Normal (ULN); total bilirubin >1.5×ULN) in the past 6 months;    -   Previous exposure or past infection caused by Mycobacterium        tuberculosis;    -   The subject has an acute infection;    -   The subject has a history of repeated, chronic or opportunistic        infections that, in the opinion of the investigator and/or GSK        medical monitor, places the subject at an unacceptable risk as a        participant in this trial;    -   The subject has a history of malignancy, except for surgically        cured basal cell carcinoma or females with cured cervical        carcinoma (>2 yrs prior);    -   The subject has a history of human immunodeficiency virus (HIV)        or other immunodeficiency disease;    -   The subject whose calculated creatinine clearance is less than        50 ml/min;    -   The subject has significant cardiac, pulmonary, metabolic,        renal, hepatic or gastrointestinal conditions that, in the        opinion of the investigator and/or GSK medical monitor, places        the subject at an unacceptable risk as a participant in this        trial;    -   The subject has taken cyclosporine, leflonomide, cyclophophamide        or azathioprine within 1 month of screening. Subjects that have        taken cyclosporine, leflonomide, cyclophophamide or azathioprine        in the past must have recovered from all drug related adverse        events;    -   The subject has taken gold salts or d-penicillamine within 1        month prior to screening. Subjects that have taken gold salts or        d-penicillamine in the past must have recovered from all drug        related adverse events;    -   The subject has received intra-articular glucocorticoids within        1 month of screening;    -   Recent history of bleeding disorders, anaemia, peptic ulcer        disease, haematemesis or gastrointestinal bleeding;    -   Subjects with a history of haematological disease or acquired        platelet disorders, including drug-induced thrombocytopaenia,        acute idiopathic thrombocytopaenia or von Willebrand's disease;    -   Subjects with a known risk of intra-cranial haemorrhage        including Central Nervous System (CNS) surgery within the last        12 months, arterial vascular malformations, aneurysms,        significant closed head trauma within 6 months or any other        incident the investigator and/or medical monitor considers to be        relevant;    -   The subject has Hb <10 g/deciliter (dL) and platelet count        <150×109/Liter (L);    -   Donation of blood in excess of 500 ml within a 56 day period        prior to dosing;    -   An unwillingness of male subjects to abstain from sexual        intercourse with pregnant or lactating women; or an        unwillingness of the male subject to use a condom with        spermicide in addition to having their female partner use        another form of contraception such as an interuterine device        (IUD), diaphragm with spermicide, oral contraceptives,        injectable progesterone, subdermal implants of levonorgestrel or        a tubal ligation if the woman could become pregnant for at least        12 weeks after dosing;    -   An unwillingness of female subject of child bearing potential to        use adequate contraception, as defined in the study restriction        section. If necessary, women of non-child bearing potential        (i.e. post-menopausal or surgically sterile e.g. tubal ligation        or hysterectomy or bilateral oophorectomy) will be confirmed.        Postmenopausal status will be confirmed by serum follicle        stimulating hormone (FSH) and oestradiol concentrations at        screening. Surgical sterility will be defined as females who        have had a documented hysterectomy, tubal ligation or bilateral        oophorectomy;    -   The subject has a history of use of drugs of abuse within 12        months prior to screening;    -   History of regular alcohol consumption exceeding average weekly        intake of greater than 21 units or an average daily intake of        greater than 3 units (males) or an average weekly intake of        greater than 14 units or an average daily intake of greater than        2 units (females). Subjects who regularly consume more than 12        units of alcohol in a 24 h period will also be excluded. 1 unit        is equivalent to a half-pint (220 ml) of beer/lager or 1 (25 ml)        measure of spirits or 1 glass (125 ml) of wine;    -   Positive pregnancy test or lactating at screening;    -   Participation in a trial with any investigational drug within 3        months or 5 half-lives (whichever is longer) before.

Study Design: This is a randomized, double-blinded, placebo-controlledadaptive, dose finding study to investigate the safety, tolerability,PK, PD and efficacy of single and repeat intravenous infusions of acompound of Formula (I)-(XV) or Group A in patients with activerheumatoid arthritis. The study is divided into 2 parts: Part A is anadaptive, dose finding phase which will provide safety, tolerability, PKand PD on single intravenous infusions. Part B is a repeat dose phasewhich will provide safety, tolerability, PK, PD and efficacy followingrepeat intravenous infusions of a selected dose level.

Primary Outcome Measures:

-   -   Safety and Tolerability following single ascending doses of a        compound of Formula (I)-(XV) or Group A at 1 month and following        3 repeat doses of a compound of Formula (I)-(XV) or Group A at 3        months. Clinical Efficacy (DAS28 score) of a compound of Formula        (I)-(XV) or Group A at 1 month

Secondary Outcome Measures:

-   -   Weighted mean DAS28 after single and repeat intravenous doses    -   Plasma PK parameters of a compound of Formula (I)-(XV) or Group        A after single and repeat intravenous doses including free, and        bound a compound of Formula (I)-(XV) or Group A (serum)        concentrations, AUC_((0-∞)), C_(max), clearance, volume of        distribution and accumulation ratio    -   DAS28 and EULAR response criteria after single and repeat        intravenous doses    -   ACR20/ACR50/ACR70 response after single and repeat intravenous        doses    -   Number of swollen joints assessed using 28-joint counts    -   Number of tender/painful joints assessed using 28-joint counts    -   Subject's pain assessment    -   Physician's global assessment of arthritis condition    -   Patients' global assessment of arthritis condition    -   Functional disability index (Health Assessment Questionnaire)    -   C-reactive Protein (CRP)    -   ESR    -   Global Fatigue Index    -   HAQ disability index    -   Pharmacodynamic biomarkers after single and repeat intravenous        doses    -   Characteristic AUC₅₀ and EC₅₀ for clinical endpoint changes with        plasma exposure model, as assessed by sigmoid E_(max) and        indirect response PK/PD models.    -   Immunogenicity (Human anti-compound of Formula (I)-(XV) or Group        A antibodies)        Phase II Clinical Trial of the Safety and Efficacy of Compounds        of Formula (I)-(XV) or Group A in Patients with Severe,        Recalcitrant, Plaque-type Psoriasis.

The purpose of this phase II trial is to investigate the safety,efficacy, and tolerability of a compound of Formula (I)-(XV) or Group Ain patients with severe, recalcitrant, plaque-type psoriasis.

Patients: Eligible subjects will be men and women between the ages of 18and 75.

Criteria:

Inclusion Criteria:

-   -   The patient has severe, recalcitrant, plaque-type psoriasis and        has failed at least 1 systemic therapy (for the purposes of this        study psoralen with ultraviolet light A is considered to be a        systemic therapy);    -   The patient has psoriatic involvement of at least 10% of BSA;    -   The patient has a PSGA score of 4 or greater;    -   The patient, if a woman, is surgically sterile or 2 years        postmenopausal, or if of childbearing potential is currently        using a medically accepted method of contraception, and agrees        to continue use of this method for the duration of the study        (and for 30 days after participation in the study). Acceptable        methods of contraception include: abstinence, steroidal        contraceptive (oral, transdermal, implanted, or injected) in        conjunction with a barrier method, or intrauterine device (IUD);    -   The patient, if a main, is surgically sterile, or if capable of        producing offspring, is currently using an approved method of        birth control, and agrees to continued use of this method for        the duration of the study (and for 60 days after taking the last        dose of a compound of Formula (I)-(XV) or Group A because of the        possible effects on spermatogenesis);    -   The patient must be willing and able to comply with study        procedures and restrictions and willing to return to the clinic        for the follow-up evaluation as specified in this protocol.        Exclusion Criteria:    -   The patient has received treatment with systemic psoriasis        treatments (specifically, retinoids, methotrexate, cyclosporine        A, etanercept, efalizumab, other biological agents or other        immunomodulators) within 4 weeks, or UV based therapy within 2        weeks, or alefacept within 6 weeks of the planned 1st day of        study treatment;    -   The patient has received treatment with potent CYP3A4 inhibitors        including cyclosporine, clotrimazole, fluconazole, itraconazole,        ketoconazole, voriconazole, erythromycin, clarithromycin, and        troleandomycin, human immunodeficiency virus (HIV) protease        inhibitors, or nefazodone within 1 week (7 days) of the planned        1st day of study treatment;    -   The patient is currently receiving warfarin;    -   The patient has hypersensitivity to a compound of Formula        (I)-(XV) or Group A or any component of a compound of Formula        (I)-(XV) or Group A;    -   The patient has one or more of the following serum chemistry        values as determined at the screening visit (visit 1):    -   bilirubin levels greater than 2 times the upper limit of normal        (ULN);    -   ALT or AST levels greater than 2 times the ULN;    -   serum creatinine levels or more than 2 mg/dL;    -   The patient requires current treatment for HIV with protease        inhibitors;    -   The patient is taking medication for a clinical diagnosis of        gastrointestinal ulceration or has experienced melena or        hematoemesis in the previous 3 weeks;    -   The patient is a woman who is pregnant or lactating;    -   The patient has received treatment with an investigation drug        within 4 weeks of the planned 1st day of study treatment.

Study Design: This is an exploratory, open-label, nonrandomized,dose-escalation study of the efficacy, safety, and tolerability of acompound of Formula (I)-(XV) or Group A in patients with severe,recalcitrant, plaque-type psoriasis.

Phase II Clinical Trial of the Safety and Efficacy of Compounds ofFormula (I)-(XV) or Group A for Prophylaxis of Acute Rejection afterRenal Transplantation

The standard immunosuppressive treatment after renal transplantation isa combination of tacrolimus, mycophenolate mofetil, and prednisolone.With this regimen the incidence of acute rejection within the first sixmonths after transplantation can drop to about 20%. The main challengeat present remains to improve long-term outcome by preventing chronicallograft nephropathy (CAN). Since acute rejection is a strong predictorof CAN, a further decrease in the incidence of acute rejection canimprove the long-term graft survival. The purpose of this phase IIclinical trial is to investigate the effectiveness and safety of acompound of Formula (I)-(XV) or Group A for prophylaxis of acuterejection after renal transplantation.

Patients: Eligible subjects will be men and women ages 18 and older

Criteria:

Inclusion Criteria:

-   -   Renal transplant recipients;    -   Signed, dated, and witnessed IRB approved informed consent;        Exclusion Criteria:    -   Pregnancy;    -   Living donor, who is HLA identical;    -   Hemolytic uremic syndrome as original kidney disease;    -   Focal segmental glomerulosclerosis that had recurred in a        previous graft;    -   More than two previously failed grafts and/or PRA >85%;    -   Diabetes mellitus that is currently not treated with insulin;    -   Total white blood cell count <3,000/mm3 or platelet count        <75,000/mm3;    -   Active infection with hepatitis B, hepatitis C, or HIV;    -   History of tuberculosis.

Study Design: This is a randomized, double blind, placebo controlledintervention study on the efficacy and safety of the prophylactic use ofa compound of Formula (I)-(XV) or Group A. One group will receive asingle dose of a compound of Formula (I)-(XV) or Group A intravenouslyat the time of transplantation, and the other group receives a placeboinfusion.

Primary Outcome:

-   -   To determine the incidence and severity of biopsy-confirmed        acute rejection within the first six months after        transplantation

Secondary Outcomes:

-   -   Renal function as estimated by the endogenous creatinine        clearance at 6 months    -   Occurrence of chronic allograft nephropathy at 6 months    -   Cumulative incidence of infections and malignancies at 6 months    -   Medical costs during the first 6 months after transplantation    -   Patient and graft survival        Phase II Clinical Trial of the Safety and Tolerability of a        compound of Formula (I)-(XV) or Group A in Patients with Active        Ulcerative Colitis (UC)

The purpose of this phase II trial is to investigate the safety,tolerability of a compound of Formula (I)-(XV) or Group A regimen inpatients with active ulcerative colitis.

Patients: Eligible subjects will be men and women aged 18 and older

Criteria:

Inclusion Criteria:

-   -   Active UC on 5-ASA therapy and also treated with 6-MP and/or        corticosteroids or who have previously been treated with AZA,        6-MP or corticosteroids and could not tolerate them;    -   Mayo score of 6 to 10 points with moderate to severe disease on        endoscopy (Mayo score of at least 2) performed ≦14 days of study        drug administration;    -   Subjects on the following medications may be enrolled into the        study if the medications were according to the following        schedules prior to study drug administration and if no changes        are anticipated during the study;        -   prednisolone ≦20 mg daily (or equivalent) (dose must be            stable for at least 2 weeks prior to study drug            administration);        -   5-ASA (dose must be stable for at least 4 weeks prior to            study drug administration);        -   AZA or 6-MP (dose must be stable for at least 3 months prior            to study drug administration);        -   Rectal steroids or 5-ASA (must have been stable for at least            4 weeks prior to study drug);    -   Subjects using rectal medications must have visible disease on        sigmoidoscopy at ≧20 cm;    -   Screening laboratory values must meet certain criteria:        -   Women must be postmenopausal (>12 months without menses) or            surgically sterile (e.g., by hysterectomy and/or bilateral            oophorectomy) or must be using effective contraception            (e.g., oral contraceptives, intrauterine device (IUD),            double barrier method of condom and spermicidal) for at            least 4 weeks prior to study drug administration and agree            to continue contraception for the duration of their            participation in the study; and        -   Sexually active male subjects must use a barrier method of            contraception during the duration of the study            Exclusion Criteria:    -   Anti-TNF therapy within 8 weeks before study drug        administration;    -   Any experimental therapy more therapy ≦4 weeks before study drug        administration;    -   Prior treatment with any monoclonal antibody or        immunoglobulin-based fusion proteins ≦8 weeks prior to study        treatment;    -   Presence of Cushing's syndrome;    -   Toxic megacolon or fulminant disease likely to require        colectomy;    -   Contraindication to colonoscopy or sigmoidoscopy;    -   Primary or secondary immunodeficiency;    -   Autoimmune disease besides UC, with the exceptions of Sjogren's        syndrome or hypothyroidism;    -   History of malignancy, excluding adequately treated and cured        basal or squamous cell of the skin, or cervical carcinoma in        situ;    -   Major psychiatric disease (subjects with stable depression        receiving appropriate management will be permitted in the        study);    -   Evidence of acute or chronic infection as evidenced by:    -   stool culture positive for pathogens and/or Clostridium        difficile toxin;    -   findings on Screening chest radiography such as pulmonary        infiltrate(s) or adenopathy;    -   current treatment for tuberculosis infection, clinical or        radiological evidence of active TB, or for subjects in North        America, a positive PPD without prior prophylaxis;    -   Herpes zoster ≦3 months prior to study drug administration;    -   active infectious disease requiring i.v. antibiotics within 4        weeks prior to study treatment or oral antibiotics at the time        of enrollment;    -   HIV or AIDS;    -   positive tests for HBV, or HCV indicating active or chronic        infection;    -   Clinically significant cardiac disease requiring medication,        unstable angina, myocardial within 6 months, or congestive heart        failure;    -   Arrhythmia requiring active therapy, with the exception of        clinically insignificant or minor conduction abnormalities;    -   History of cerebrovascular disease requiring        medication/treatment;    -   Anticoagulation therapy or a known bleeding disorder;    -   Seizure disorder requiring active therapy;    -   Known drug or alcohol abuse;    -   Pregnant or nursing;    -   Any underlying medical condition that in the Principal        Investigator's opinion will make the study drug hazardous to the        subject or would obscure the interpretation of treatment        efficacy or safety; or    -   Inability or unwillingness to return for Follow-up visits and        comply with study protocol

Primary Outcome Measures:

-   -   Change in Mayo score at Day 57 compared with Screening

Secondary Outcome Measures:

-   -   Remission rate

Study Design: This is a phase II, double-blind, placebo-controlled,randomized, multi-dose study of a compound of Formula (I)-(XV) or GroupA in subjects with active UC experiencing flare. All subjects will haveactive disease while on a 5-ASA containing medication and are either onstable doses of corticosteroids and/or azathioprine or 6-mercaptopurine,or who have previously been on these medications but could not toleratethem. Flare is defined as a Mayo score of 6 to 10 with moderate tosevere disease activity on endoscopy (Mayo endoscopic subscore of atleast 2) within 2 weeks of receiving study drug administration. Doses ofpermitted concomitant medications (corticosteroids, azathioprine (AZA),6-mercaptopurine (6-MP), and 5-aminosalicylates (5-ASA) containingcompounds) should remain constant during the course of the study.Subjects will be randomized to receive placebo or a compound of Formula(I)-(XV) or Group A intravenously on Days 1, 15, 29, and 43. Allsubjects will be seen in the clinic at regular intervals up to Day 85for safety, efficacy, pharmacokinetic, and/or pharmacodynamicassessments. All subjects will be contacted 70 days after the last doseof study drug. Assessment of safety will be determined by vital signmeasurements, clinical laboratory tests, physical examinations,immunogenicity assessments, chest x-ray, electrocardiograms, and theincidence and severity of treatment emergent adverse events. The primaryclinical assessment of activity will be determined by the change in Mayoscore at Day 57 compared with Screening. Secondary endpoints includedetermination of remission rate by the mayo score at Day 57, evaluationof mucosal healing and change from baseline in the IBDQ score.

Phase II Clinical Trial of the Safety and Efficacy of Compounds ofFormula (I)-(XV) or Group A in Patients with Multiple Sclerosis

The purpose of this phase II trial is to investigate the safety,efficacy and tolerability of a compound of Formula (I)-(XV) or Group Ain patients with Relapsing-Remitting Multiple Sclerosis.

Patients: Eligible subjects will be men and women between the ages of 18and 65.

Criteria:

Inclusion Criteria:

-   -   Have a definite diagnosis of Relapsing remitting Multiple        Sclerosis    -   Have a history of at least 1 of the following: a. A minimum of 2        relapses of MS within the previous 2 years but not within the        1-month period prior to screening. b. A relapse of MS within the        previous 6 months but not within the 1-monthperiod prior to        screening

Exclusion Criteria:

-   -   Have a CNS disease (e.g., CNS lymphoma, systemic lupus        erythematous)    -   Have significant bulbar involvement of MS or other neurologic        deficits    -   Have a decubitus ulcer    -   Have received immunomodulatory therapies within 3 months of        screening

Primary Outcome Measures:

-   -   The cumulative number of newly Gd-enhancing T1-weighted lesions        on cranial MRIs through week 23

Secondary Outcome Measures:

-   -   The total number of relapses of MS through week 23; change from        baseline in Expanded Disability Status Scale (EDSS) score at        week 23

Study Design: This is a phase II, double-blind, placebo-controlled,randomized, dose-ranging study of multiple subcutaneous injections of acompound of Formula (I)-(XV) or Group A in patients withrelapsing-remitting multiple sclerosis. Patients will receivesubcutaneous injections of a compound of Formula (I)-(XV) or Group A orplacebo at weeks 0, 1, 2, 3, 7, 11, 15, and 19 or 100.

Pharmaceutical Compositions

Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a compound of Formula (I)-(XV) orGroup A is dissolved in DMSO and then mixed with 10 mL of 0.9% sterilesaline. The mixture is incorporated into a dosage unit form suitable foradministration by injection.

In another embodiment, the following ingredients are mixed to form aninjectable formulation:

Ingredient Amount Compound of Formula (I)-(XV) or Group A 1.2 g sodiumacetate buffer solution (0.4 M) 2.0 mL HCl (1 N) or NaOH (1 M) q.s. tosuitable pH water (distilled, sterile) q.s. to 20 mL

All of the above ingredients, except water, are combined and stirred andif necessary, with slight heating if necessary. A sufficient quantity ofwater is then added.

Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I)-(XV) or Group A is mixed with 750 mg of starch.The mixture is incorporated into an oral dosage unit, such as a hardgelatin capsule, which is suitable for oral administration.

In another embodiment, the following ingredients are mixed intimatelyand pressed into single scored tablets.

Ingredient Quantity per tablet, mg compound of Formula (I)-(XV) or GroupA 200 Cornstarch 50 croscarmellose sodium 25 Lactose 120 magnesiumstearate 5

In yet another embodiment, the following ingredients are mixedintimately and loaded into a hard-shell gelatin capsule.

Quantity per Ingredient tablet, mg compound of Formula (I)-(XV) or GroupA 200 lactose, spray-dried 148 magnesium stearate 2

In yet another embodiment, the following ingredients are mixed to form asolution/suspension for oral administration:

Ingredient Amount Compound of Formula (I)-(XV) or Group A 1 g AnhydrousSodium Carbonate 0.1 g Ethanol (200 proof), USP 10 mL Purified Water,USP 90 mL Aspartame 0.003 g

Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (I)-(XV) or Group Awith 420 mg of powdered sugar mixed with 1.6 mL of light corn syrup, 2.4mL distilled water, and 0.42 mL mint extract. The mixture is gentlyblended and poured into a mold to form a lozenge suitable for buccaladministration.

Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (I)-(XV) or Group A is mixed with 50 mg ofanhydrous citric acid and 100 mL of 0.9% sodium chloride solution. Themixture is incorporated into an inhalation delivery unit, such as anebulizer, which is suitable for inhalation administration.

Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (I)-(XV) or Group A is mixed with 2.5 g ofmethylcelluose (1500 mPa), 100 mg of methylparapen, 5 g of glycerin and100 mL of purified water. The resulting gel mixture is then incorporatedinto rectal delivery units, such as syringes, which are suitable forrectal administration.

Suppository Formulation

A suppository of total weight 2.5 g is prepared by mixing a compound ofFormula (I)-(XV) or Group A with Witepsol™H-15 (triglycerides ofsaturated vegetable fatty acid; Riches-Nelson, Inc., New York), and hasthe following composition:

Quantity per Ingredient suppository, mg compound of Formula (I)-(XV) orGroup A 500 Witepsol ® H-15 balance

Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I)-(XV) or Group A is mixed with 1.75 g ofhydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropylmyristate and 100 mL of purified alcohol USP. The resulting gel mixtureis then incorporated into containers, such as tubes, which are suitablefor topical administration.

Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of Formula (I)-(XV) or Group A is mixed with 0.9 g of NaCl in100 mL of purified water and filtered using a 0.2 micron filter. Theresulting isotonic solution is then incorporated into ophthalmicdelivery units, such as eye drop containers, which are suitable forophthalmic administration.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

1. A pharmaceutical composition comprising a pharmaceutically acceptablediluent, excipient or binder, and a compound of Formula (XIV):

wherein: X is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl whereincycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with at least one R₃; Y is a bond, C₁-C₆alkyl, C₂-C₆alkenyl,NR₂, O, S, NR₂(C₁-C₆alkyl), O(C₁-C₆alkyl), S(C₁-C₆alkyl),NR₂(C₂-C₆alkenyl), O(C₂-C₆alkenyl), or S(C₂-C₆alkenyl); whereinC₁-C₆alkyl or C₂-C₆alkenyl are optionally substituted with at least oneR₃; Z is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl whereincycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with at least one R_(4.); each R₁ is independently selectedfrom H, F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃ -OCF₃, OR₉, C₁-C₆alkyl,C₃-C₈cycloalkyl, C₁-C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, optionallysubstituted O-aryl, optionally substituted heteroaryl, —NHS(═O)₂R₈,—S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃, —C(═O)NHS(═O)₂R₈,—S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈, —N(R₉)C(═O)N(R₉)₂,—N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈, —OC(═O)N(R₉)₂, —CON(R₉)₂,—SR₈, —S(═O)R₈, and —S(═O)₂R₈; R₂ is H, C₁—C₆alkyl, or C₃-C₈cycloalkyl;R₃ and R₄ are each independently selected from F, Cl, Br, I, —CN, —NO₂,—OH, —CF₃, —OCF₃, —OR₉, C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁-C₆heteroalkyl,C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl, optionally substituted aryl,optionally substituted O-aryl, optionally substituted heteroaryl,—NHS(═O)₂R₈, —S(═O)₂N(R₉)₂, —N(R₉)S(═O)₂N(R₉)₂, —C(═O)CF₃,—C(═O)NHS(═O)₂R₈, —S(═O)₂NHC(═O)R₈, —N(R₉)₂, —N(R₉)C(═O)R₈,—N(R₉)C(═O)N(R₉)₂, —N(R₉)C(═O)OR₈, —CO₂R₉, —C(═O)R₈, —OC(═O)R₈,—OC(═O)N(R₉)₂, —CON(R₉)₂, —SR₈, —S(═O)R₈, and —S(═O)₂R₈; or two R₃together with the atoms to which they are attached form aheterocycloalkyl group having at least one O, NH, or S; each R₈ isindependently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl,phenyl, and benzyl; each R₉ is independently selected from H,C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₈cycloalkyl, phenyl, and benzyl; orpharmaceutically acceptable salt, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof.
 2. The pharmaceuticalcomposition of claim 1 wherein Y is C₁-C₆alkyl, C₂-C₆alkenyl, NR₂,NR₂(C₁-C₆alkyl), or NR₂(C₂-C₆alkenyl).
 3. The pharmaceutical compositionof claim 2 wherein Y is C₁-C₆alkyl, NR₂, or NR₂(C₁-C₆alkyl).
 4. Thepharmaceutical composition of claim 3 wherein Y is NR₂(C₁-C₆alkyl). 5.The pharmaceutical composition of claim 4 wherein R₂ is H.
 6. Thepharmaceutical composition of claim 5 wherein R₁ is H.
 7. Thepharmaceutical composition of claim 6 wherein Z is aryl or heteroaryl,wherein aryl or heteroaryl is optionally substituted with at least oneR₄.
 8. The pharmaceutical composition of claim 7 wherein Z is aryloptionally substituted with at least one R₄.
 9. The pharmaceuticalcomposition of claim 8 wherein Z is phenyl substituted with at least oneR₄.
 10. The pharmaceutical composition of claim 9 wherein R₄ is F, Cl,Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉, —N(R₉)₂,C₁-C₆alkyl,C₃-C₈cycloalkyl, C₁C₆heteroalkyl, C₁-C₆haloalkyl, C₂-C₈heterocycloalkyl,optionally substituted aryl, or optionally substituted heteroaryl. 11.The pharmaceutical composition of claim 10 wherein R₄ is F, Cl, or Br.12. The pharmaceutical composition of claim 7 wherein X is aryl orheteroaryl wherein aryl or heteroaryl is optionally substituted with atleast one R₃.
 13. The pharmaceutical composition of claim 12 wherein Xis aryl optionally substituted with at least one R₃.
 14. Thepharmaceutical composition of claim 13 wherein X is phenyl substitutedwith at least one R₃.
 15. The pharmaceutical composition of claim 14wherein R₃ is F, Cl, Br, I, —CN, —NO₂, —OH, —CF₃, —OCF₃, —OR₉—N(R₉)₂,C₁-C₆alkyl, C₃-C₈cycloalkyl, C₁C₆heteroalkyl, C₁-C₆haloalkyl,C₂-C₈heterocycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; or two R₃ together with the atoms to which theyare attached form a heterocycloalkyl group having at least one O, NH, orS.
 16. The pharmaceutical composition of claim 15 wherein R₃ is F, Cl,Br, —OH, —CF₃, —OCF₃, —OR₉, —N(R₉)₂,C₁-C₆alkyl, or C₁-C₆heteroalkyl; ortwo R₃ together with the atoms to which they are attached form aheterocycloalkyl group having at least one O, NH, or S.
 17. Thepharmaceutical composition of claim 16 wherein two R₃ together with theatoms to which they are attached form a heterocycloalkyl group having atleast one O, NH, or S.
 18. The pharmaceutical composition of claim 1wherein the compound of Formula (XIV) is: